Bio

Bio


Josh Knowles is a physician-scientist and the overall theme my research has been the genetic basis of cardiovascular disease across the continuum from Discovery to the development of Model Systems to the Translation of these findings to the clinic and most recently to the Public Health aspect of genetics. He completed his MD-PhD at UNC with Prof. Nobuyo Maeda and Nobel Laureate Oliver Smithies. He did Internal Medicine residency and Cardiology fellowship training at Stanford working with Dr. Tom Quertermous. Currently his Discovery and basic translational efforts center on understanding the genetic basis of insulin resistance using GWAS studies coupled with exploration in model systems. His clinical translational focus is on Familial Hypercholesterolemia (FH) and he is the volunteer Chief Medical Advisor of the FH Foundation (FHF) which is a patient-led organization dedicated to increasing awareness of FH, identifying and treating patients with FH and screening family members to prevent deleterious outcomes. He helped lead the FHF efforts to establish a national patient registry (CASCADE FH), apply for an ICD10 code for FH and is now using cutting-edge “big-data” approaches to identify previously undiagnosed FH patients in electronic medical records (FIND FH). He has published over 90 papers with research projects currently funded by the National Institutes of Health, the American Heart Association and the Doris Duke Charitable Foundation.

Clinical Focus


  • Cardiology
  • Insulin Resistance
  • Familial Hypercholesterolemia
  • Cardiovascular Disease
  • Genetics

Academic Appointments


Administrative Appointments


  • Co-Section Chief. Metabolism and Insulin Signaling, Stanford Diabetes Research Center` (2017 - Present)
  • Program Director, Cardiovascular Medicine Fellowship Program (2018 - Present)
  • Co-Director, Translational Investigator Program (2017 - Present)
  • Chief, Translational Medicine, The FH Foundation (2012 - Present)

Honors & Awards


  • National Innovative Research Award, AHA
  • Dean's Fellowship, Stanford (2005)
  • Clinical Scholar, Doris Duke Charitable Foundation (6/1/16-6/1/19)
  • Fellowship Award, Future Leaders in CV Medicine (2006)
  • Alderman Award for Excellence in Clinical Research, Stanford Cardiovascular Medicine (2008, 2009)
  • Diplomate, National Lipid Association (2012)
  • Fellow, AHA (2012)
  • Fellow, ACC (2012)
  • National Fellow to Faculty Transition Award, AHA (7/1/10-7/1/15)

Boards, Advisory Committees, Professional Organizations


  • Board Member, The FH Foundation (2012 - Present)

Professional Education


  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2010)
  • Fellowship:Stanford University School of Medicine (2010) CA
  • Residency:Stanford University School of Medicine (2005) CA
  • Medical Education:University of North Carolina - Chapel Hill (2003) NC
  • PhD, University of North Carolina, Chapel Hill, Genetics and Molecular Biology (2001)

Community and International Work


  • The FH Foundation

    Topic

    Familial Hypercholesterolemia

    Partnering Organization(s)

    The FH Foundation

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Arbor Free Clinic

    Location

    Bay Area

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Research & Scholarship

Current Research and Scholarly Interests


The overall theme of my work is to understand the genetic basis of complex cardiovascular diseases such as coronary disease and insulin resistance. Currently, I am involved in genome wide association (GWA) studies of coronary disease through the NIH-funded ADVANCE study and of insulin resistance through the international GENESIS project. After using the GWA approach to discover and validate interesting candidate genes, I hope to explore the biology underlying these genes and pathways using cell culture and in vivo model systems. I am also using iPSC technology (induced pluripotent stem cells) to develop model systems for the study of insulin resistance through the NIH-funded GENESiPS project.

I also have a strong interest in developing tools to help translate newly emerging genetic data into clinical practice and am currently the PI of a randomized trial where we are examining whether we can improve patient coronary disease risk factor profiles by giving them information about their inherited risk of coronary disease.

Clinically, I am interested in the care of patients with inherited cardiovascular conditions. In particular I am focused on individuals with Familial Hypercholesterolemia. I also have an interest in treating Hypertrophic Cardiomyopathy. I take care of these patients in the Stanford Center for Inherited Cardiovascular Disease.

Clinical Trials


  • Relationship Between Insulin Resistance and Statin Induced Type 2 Diabetes, and Integrative Personal Omics Profiling Recruiting

    There is general agreement that statin-treatment of patients with high cholesterol can increase the incidence of type 2 diabetes (T2DM) in some individuals. This research proposal will study what metabolic characteristics and variables (for example high cholesterol or high triglycerides or both) will identify those people at highest risk of statin-induced T2DM. The investigators will evaluate how the medication atorvastatin (trade name Lipitor) works in regards to its effect on insulin action and insulin sensitivity to help further understand the possible cause of the increased occurrences of T2DM in people who are at risk for T2DM. Under Dr. Snyder, a Co-director of the study, samples will be collected for integrated Personal Omics Profiling (iPOP), a monitoring approach developed by Dr. Snyder and his research colleagues. The investigators propose to analyze iPOP of individuals who participate in this study during and after taking the statin. In this pilot study, analysis will be done on previously-known drug effectiveness but also untargeted drug's effectiveness, (other unknown benefits this medication may have) and drug effects such as those seen in some participants when given a statin. The hope then is to obtain a better understanding of how to perform a personal omics profile when taking drugs, which would lead to develop better use of drugs. .

    View full details

  • Personal Genomics for Preventive Cardiology Not Recruiting

    The purpose of this study is to see if providing information to a person on their inherited (genetic) risk of cardiovascular disease (CVD) helps to motivate that person to change their diet, lifestyle or medication regimen to alter their risk.

    Stanford is currently not accepting patients for this trial. For more information, please contact Josh Knowles, 650-804-2526.

    View full details

Teaching

Stanford Advisees


Publications

All Publications


  • The role of insulin as a key regulator of seeding, proliferation, and mRNA transcription of human pluripotent stem cells. Stem cell research & therapy Shahbazi, M., Cundiff, P., Zhou, W., Lee, P., Patel, A., D'Souza, S. L., Abbasi, F., Quertermous, T., Knowles, J. W. 2019; 10 (1): 228

    Abstract

    BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) show a great promise as a renewable source of cells with broad biomedical applications. Since insulin has been used in the maintenance of hiPSCs, in this study we explored the role of insulin in culture of these cells.METHODS: We report conditions for insulin starvation and stimulation of hiPSCs. Crystal violet staining was used to study the adhesion and proliferation of hiPSCs. Apoptosis and cell cycle assays were performed through flow cytometry. Protein arrays were used to confirm phosphorylation targets, and mRNA sequencing was used to evaluate the effect of transcriptome.RESULTS: Insulin improved the seeding and proliferation of hiPSCs. We also observed an altered cell cycle profile and increase in apoptosis in hiPSCs in the absence of insulin. Furthermore, we confirmed phosphorylation of key components of insulin signaling pathway in the presence of insulin and demonstrated the significant effect of insulin on regulation of the mRNA transcriptome of hiPSCs.CONCLUSION: Insulin is a major regulator of seeding, proliferation, phosphorylation and mRNA transcriptome in hiPSCs. Collectively, our work furthers our understanding of human pluripotency and paves the way for future studies that use hiPSCs for modeling genetic ailments affecting insulin signaling pathways.

    View details for DOI 10.1186/s13287-019-1319-5

    View details for PubMedID 31358052

  • Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. The lancet. Diabetes & endocrinology Ray, K. K., Colhoun, H. M., Szarek, M., Baccara-Dinet, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Lopes, R. D., Moryusef, A., Murin, J., Pordy, R., Ristic, A. D., Roe, M. T., Tunon, J., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P. G., ODYSSEY OUTCOMES Committees and Investigators, Schwartz, G. G., Steg, P. G., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Lopes, R. D., Gotcheva, N. N., Prieto, J., Yong, H., Lopez-Jaramillo, P., Pecin, I., Reiner, Z., Ostadal, P., Viigimaa, M., Nieminen, M. S., Chumburidze, V., Marx, N., Danchin, N., Liberopoulos, E., Montenegro Valdovinos, P. C., Tse, H., Kiss, R. G., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H. S., Kim, S., Erglis, A., Laucevicius, A., Kedev, S., Yusoff, K., Ramos Lopez, G. A., Alings, M., Halvorsen, S., Correa Flores, R. M., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tunon, J., de Silva, H. A., Hagstrom, E., Landmesser, U., Chiang, C., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Vogel, R., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. J., Tricoci, P., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M. C., Brennan, J. M., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C. N., Hlatky, M. A., Jordan, J. D., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H. G., Patel, C. B., Bernardez-Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Schuyler Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Trotter, C., Van Diepen, S., Wilson, M. D., Yan, A. T., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Hominal, M. A., Montana, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, O., Codutti, O. R., Jure, H. O., Bono, J. O., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. D., Colombo, H. R., Liberman, A., Fuentealba, V., Luciardi, H. L., Waisman, G. D., Berli, M. A., Garcia Duran, R. O., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Hii, C. L., Shaw, J., Arstall, M. A., Horowitz, J., Ninio, D., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. G., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Delle-Karth, G., Frey, B., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. C., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Kulic, M., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Nigro Maia, L., Rech, R., Rossi, P. R., Cerqueira, M. J., Duda, N., Kalil, R., Kormann, A., Abrantes, J. A., Pimentel Filho, P., Soggia, A. P., de Santos, M. O., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Manenti, E. R., Precoma, D. B., Moura Jorge, J. C., de B Silva, P. G., Silveira, J. A., Saporito, W., Marin-Neto, J. A., Feitosa, G. S., Ritt, L. E., de Souza, J. A., Costa, F., Souza, W. K., Reis, H. J., Machado, L., Ayoub, J. C., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Gospodinov, M., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Lutchmedial, S., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Huynh, T., Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yanez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zhong, Y., Zheng, Y., Li, X., Peng, D., Zhao, S., Li, Y., Liu, X., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Xiang, M., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Sanchez Vallejo, G., Luna Botia, D. C., Botero Lopez, R., Molina De Salazar, D. I., Cadena Bonfanti, A. J., Cotes Aroca, C., Diego Higuera, J., Blanquicett, M., Barrera Silva, S. I., Garcia Lozada, H. J., Coronel Arroyo, J. A., Accini Mendoza, J. L., Fernandez Ruiz, R. L., Quintero Ossa, A. M., Manzur Jatin, F. G., Sotomayor Herazo, A., Castellanos Parada, J., Suarez Arambula, R., Urina Triana, M. A., Fernandez Trujillo, A. M., Strozzi, M., Car, S., Jeric, M., Milicic, D., Bencic, M. L., Pintaric, H., Prvulovic, D., Sikic, J., Persic, V., Mileta, D., Stambuk, K., Babic, Z., Tomulic, V., Lukenda, J., Mejic-Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Velicka, Z., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Poulsen, S. H., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bottcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Betton Johansen, P., Hald, F., Johansen, P., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P. M., Lomholdt, J. D., Klausen, I. C., Nielsen, P. K., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopold, U., Martsin, K., Jurgenson, T., Kristjan, A., Helsinki, J. K., Vikman, S., Huikuri, H., Airaksinen, J., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Machecourt, J., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefevre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Edward, K., Rauch-Krohnert, U., Stratmann, M., Appel, K., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Vohringer, H. F., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Werner, C., Marx, N., Gielen, S., Nuding, S., Winkelmann, B., Behrens, S., Sydow, K., Karakas, M., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Bocker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., WeiSSbrodt, M., Schaeufele, T., Weil, J., Voller, H., Waltenberger, J., Natour, M., Schmitt, S., Muller-Wieland, D., Steiner, S., Heidenreich, L., Offers, E., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Chachalis, G., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Fausto Ovando, S. R., Arango Benecke, J. L., Rodriguez De Leon, E. R., Yan, B. P., Siu, D. C., Turi, T., Merkely, B., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Edes, I., Muller, G., Horvath, I., Kapin, T., Szigeti, Z., Falukozy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N. R., Regella, R., Premchand, R. K., Mahajan, A., Pawar, S., Abhyanakar, A. D., Kerkar, P., Govinda, R. A., Oomman, A., Sinha, D., Patil, S. N., Kahali, D., Sawhney, J., Joshi, A. B., Chaudhary, S., Harkut, P., Guha, S., Porwal, S., Jujjuru, S., Pothineni, R. B., Monteiro, M. R., Khan, A., Iyengar, S. S., Grewal, J. S., Chopda, M., Fulwani, M. C., Patange, A., Sachin, P., Chopra, V. K., Goyal, N. K., Shinde, R., Manakshe, G. V., Patki, N., Sethi, S., Munusamy, V., Karna, S., Thanvi, S., Adhyapak, S., Patil, C., Pandurangi, U., Mathur, R., Gupta, J., Kalashetti, S., Bhagwat, A., Raghuraman, B., Yerra, S. K., Bhansali, P., Borse, R., Rahul, P., Das, S., Kumar, V., Abdullakutty, J., Saathe, S., Palimkar, P., Sathe, S., Atar, S., Shechter, M., Mosseri, M., Arbel, Y., Ehud, C., Ofer, H., Lotan, C., Rosenschein, U., Katz, A., Henkin, Y., Francis, A., Klutstein, M., Nikolsky, E., Zukermann, R., Turgeman, Y., Halabi, M., Marmor, A., Kornowski, R., Jonas, M., Amir, O., Hasin, Y., Rozenman, Y., Fuchs, S., Zvi, V., Hussein, O., Gavish, D., Vered, Z., Caraco, Y., Elias, M., Tov, N., Wolfovitz, E., Lishner, M., Elias, N., Piovaccari, G., De Pellegrin, A., Garbelotto, R., Guardigli, G., Marco, V., Licciardello, G., Auguadro, C., Scalise, F., Cuccia, C., Salvioni, A., Musumeci, G., Senni, M., Calabro, P., Novo, S., Faggiano, P., Metra, M., De Cesare, N. B., Berti, S., Cavallini, C., Puccioni, E., Galvani, M., Tespili, M., Piatti, P., Palvarini, M., De Luca, G., Violini, R., De Leo, A., Olivari, Z., Perrone Filardi, P., Ferratini, M., Racca, V., Dai, K., Shimatani, Y., Kamiya, H., Ando, K., Takeda, Y., Morino, Y., Hata, Y., Kimura, K., Kishi, K., Michishita, I., Uehara, H., Higashikata, T., Hirayama, A., Hirooka, K., Doi, Y., Sakagami, S., Taguchi, S., Koike, A., Fujinaga, H., Koba, S., Kozuma, K., Kawasaki, T., Ono, Y., Shimizu, M., Katsuda, Y., Wada, A., Shinke, T., Kimura, T., Ako, J., Fujii, K., Takahashi, T., Sakamoto, T., Nakao, K., Furukawa, Y., Sugino, H., Tamura, R., Mano, T., Uematsu, M., Utsu, N., Ito, K., Haraguchi, T., Sato, K., Ueda, Y., Nishibe, A., Fujimoto, K., Masutani, M., Yoon, J. H., Kim, H., Park, H. S., Chae, I., Kim, M. H., Jeong, M. H., Rha, S., Kim, C., Kim, H., Kim, H. Y., Hong, T., Tahk, S., Kim, Y., Busmane, A., Pontaga, N., Strelnieks, A., Mintale, I., Sime, I., Petrulioniene, Z., Kavaliauskiene, R., Jurgaitiene, R., Sakalyte, G., Slapikas, R., Norkiene, S., Misonis, N., Kibarskis, A., Kubilius, R., Bojovski, S., Lozance, N., Kjovkaroski, A., Doncovska, S., Ong, T. K., Kasim, S., Maskon, O., Kandasamy, B., Liew, H. B., Wan Mohamed, W. M., Garcia Castillo, A., Carrillo Calvillo, J., Fajardo Campos, P., Nunez Fragoso, J. C., Bayram Llamas, E. A., Alcocer Gamba, M. A., Carranza Madrigal, J., Gonzalez Salas, L. G., Lopez Rosas, E., Gonzalez Diaz, B., Salcido Vazquez, E., Nacoud Ackar, A., Llamas Esperon, G. A., Martinez Sanchez, C. R., Guerrero De Leon, M., Suarez Otero, R., Fanghanel Salmon, G., Perez Rios, J. A., Garza Ruiz, J. A., Breedveld, R. W., Feenema-Aardema, M., Borger-Van Der Burg, A., Hoogslag, P. A., Suryapranata, H., Oomen, A., Van Haelst, P., Wiersma, J. J., Basart, D., Van Der Wal, R. M., Zwart, P., Monraats, P., Van Kesteren, H., Karalis, I., Jukema, J., Verdel, G. J., Brueren, B. R., Troquay, R. P., Viergever, E. P., Al-Windy, N. Y., Bartels, G. L., Cornel, J. H., Hermans, W. R., Herrman, J. P., Bos, R. J., Groutars, R. G., Van Der Zwaan, C. C., Kaplan, R., Lionarons, R., Ronner, E., Groenemeijer, B. E., Bronzwaer, P. N., Liem, A. A., Rensing, B. J., Bokern, M. J., Nijmeijer, R., Hersbach, F. M., Willems, F. F., Gosselink, A. T., Rasoul, S., Elliott, J., Wilkins, G., Fisher, R., Scott, D., Hart, H., Stewart, R., Harding, S., Ternouth, I., Fisher, N., Wilson, S., Aitken, D., Anscombe, R., Davidson, L., Tomala, T., Nygard, O., Sparby, J. A., Andersen, K., Gullestad, L., Jortveit, J., Munk, P. S., Singsaas, E. G., Hurtig, U., Calderon Ticona, J. R., Durand Velasquez, J. R., Negron Miguel, S. A., Sanabria Perez, E. S., Carrion Chambilla, J. M., Chavez Ayala, C. A., Castillo Leon, R. P., Vargas Gonzales, R. J., Hernandez Zuniga, J. D., Camacho Cosavalente, L. A., Bravo Mannucci, J. E., Heredia Landeo, J., Llerena Navarro, N. C., Roldan Concha, Y. M., Rodriguez Chavez, V. E., Anchante Hernandez, H. A., Zea Nunez, C. A., Mogrovejo Ramos, W., Ferrolino, A., Sy, R. A., Tirador, L., Sy, R. G., Matiga, G., Coching, R. M., Bernan, A., Rogelio, G., Morales, D. D., Tan, E., Sulit, D. J., Wlodarczak, A., Jaworska, K., Skonieczny, G., Pawlowicz, L., Wojewoda, P., Busz-Papiez, B., Bednarski, J., Goch, A., Staneta, P., Dulak, E., Saminski, K., Krasowski, W., Sudnik, W., Zurakowski, A., Skorski, M., Miklaszewicz, B., Kubica, J., Andrzej Lipko, J., Kostarska-Srokosz, E., Piepiorka, M., Drzewiecka, A., Stasiewski, A., Blicharski, T., Bystryk, L., Szpajer, M., Korol, M., Czerski, T., Mirek-Bryniarska, E., Gniot, J., Lubinski, A., Gorny, J., Franek, E., Raczak, G., Szwed, H., Monteiro, P., Mesquita Bastos, J., Pereira, H. H., Martins, D., Seixo, F., Mendonca, C., Botelho, A., Caetano, F., Minescu, B., Istratoaie, O., Tesloianu, D. N., Cristian, G., Dumitrescu, S., Podoleanu, C. G., Constantinescu, M. C., Bengus, C. M., Militaru, C., Rosu, D., Parepa, I. R., Matei, A. V., Alexandru, T. M., Malis, M., Coman, I., Stanescu-Cioranu, R., Dimulescu, D., Shvarts, Y., Orlikova, O., Kobalava, Z., Barbarash, O. L., Markov, V., Lyamina, N., Gordienko, A., Zrazhevsky, K., Vishnevsky, A. Y., Gurevich, V., Stryuk, R., Lomakin, N. V., Bokarev, I., Khlevchuk, T., Shalaev, S., Khaisheva, L., Chizhov, P., Viktorova, I., Osokina, N., Shchekotov, V., Akatova, E., Chumakova, G., Libov, I., Voevoda, M. I., Tretyakova, T. V., Baranov, E., Shustov, S., Yakushin, S., Gordeev, I., Khasanov, N., Reshetko, O., Sotnikova, T., Molchanova, O., Nikolaev, K., Gapon, L., Baranova, E., Shogenov, Z., Kosmachova, E., Karpov, Y., Povzun, A., Egorova, L., Tyrenko, V. V., Ivanov, I. G., Ilya, M., Kanorsky, S., Simic, D., Ivanovic, N., Davidovic, G., Tasic, N., Asanin, M. R., Stojic, S., Apostolovic, S. R., Ilic, S., Putnikovic Tosic, B., Stankovic, A., Arandjelovic, A., Radovanovic, S., Todic, B., Balinovac, J., Dincic, D. V., Seferovic, P., Karadzic, A., Dodic, S., Dimkovic, S., Jakimov, T., Poh, K., Ong, H. Y., Tang I-Shing, J., Micko, K., Nociar, J., Pella, D., Fulop, P., Hranai, M., Palka, J., Mazur, J., Majercak, I., Dzupina, A., Fazekas, F., Gonsorcik, J., Bugan, V., Selecky, J., Kamensky, G., Strbova, J., Smik, R., Dukat, A., Zuran, I., Poklukar, J., Cernic Suligoj, N., Cevc, M., Cyster, H. P., Ranjith, N., Corbett, C., Bayat, J., Makotoko, E. M., du Toit Theron, H., Kapp, I. E., de V Basson, M. M., Lottering, H., Van Aswegen, D., Van Zyl, L. J., Sebastian, P. J., Pillay, T., Saaiman, J. A., Commerford, P. J., Cassimjee, S., Riaz, G., Ebrahim, I. O., Sarvan, M., Mynhardt, J. H., Reuter, H., Moodley, R., Vida, M., Cequier Fillat, A. R., Bodi Peris, V., Fuentes Jimenez, F., Marin, F., Cruz Fernandez, J. M., Hidalgo Urbano, R. J., Gil-Extremera, B., Toledo, P., Worner Diz, F., Garcia-Dorado, D., Iniguez, A., Tunon Fernandez, J., Gonzalez-Juanatey, J. R., Fernandez Portales, J., Civeira Murillo, F., Matas Pericas, L., Zamorano, J. L., De Mora Martin, M., Bruguera Cortada, J., Alonso Martin, J. J., Serrano Antolin, J. M., De Berrazueta Fernandez, J. R., Vazquez de Prada, J. A., Diaz Fernandez, J. F., Garcia Lledo, J. A., Cosin Sales, J., Botas Rodriguez, J., Gusi Tragant, G., Benedicto, A., Gonzalez-Juanatey, C., Camprubi Potau, M., Plaza Perez, I., De La Tassa, C. M., Loma-Osorio Rincon, P., Balaguer Recena, J., Escudier, J. M., Payeras, A. C., Alonso Orcajo, N., Valdivielso, P., Constantine, G., Haniffa, R., Tissera, N., Amarasekera, S., Ponnamperuma, C., Fernando, N., Fernando, K., Jayawardena, J., Wijeyasingam, S., Ranasinghe, G., Ekanayaka, R., Mendis, S., Senaratne, V., Mayurathan, G., Sirisena, T., Rajapaksha, A., Herath, J. I., Amarasena, N., Berglund, S., Rasmanis, G., Vedin, O., Witt, N., Mourtzinis, G., Nicol, P., Hansen, O., Romeo, S., Agergaard Jensen, S., Torstensson, I., Ahremark, U., Sundelin, T., Moccetti, T., Muller, C., Mach, F., Binde, R., Tsai, W., Ueng, K., Lai, W., Liu, M., Hwang, J., Yin, W., Hsieh, I., Hsieh, M., Lin, W. H., Kuo, J., Huang, T., Fang, C., Kaewsuwanna, P., Soonfuang, W., Jintapakorn, W., Sukonthasarn, A., Wongpraparut, N., Sastravaha, K., Sansanayudh, N., Kehasukcharoen, W., Piyayotai, D., Chotnoparatpat, P., Camsari, A., Kultursay, H., Mutlu, B., Ersanli, M., Demirtas, M., Kirma, C., Ural, E., Koldas, L., Karpenko, O., Prokhorov, A., Vakaluyk, I., Myshanych, H., Reshotko, D., Batushkin, V., Rudenko, L., Kovalskyi, I., Kushnir, M., Tseluyko, V., Mostovoy, Y., Stanislavchuk, M., Kyiak, Y., Karpenko, Y., Malynovsky, Y., Klantsa, A., Kutniy, O., Amosova, E., Tashchuk, V., Leshchuk, O., Rishko, M., Kopytsya, M., Yagensky, A., Vatutin, M., Bagriy, A., Barna, O. M., Ushakov, O., Dzyak, G., Goloborodko, B., Rudenko, A., Zheleznyy, V., Trevelyan, J., Zaman, A., Lee, K., Moriarty, A., Aggarwal, R. K., Clifford, P., Wong, Y., Iqbal, S. M., Subkovas, E., Braganza, D., Sarkar, D., Storey, R., Griffiths, H., McClure, S., Muthusamy, R., Smith, S., Kurian, J., Levy, T., Barr, C., Kadr, H., Gerber, R., Simaitis, A., Soran, H., Mathur, A., Brodison, A., Ayaz, M., Cheema, M., Oliver, R., Thackray, S., Mudawi, T., Rahman, G., Sultan, A., Sharman, D., Sprigings, D., Butler, R., Wilkinson, P., Lip, G. Y., Halcox, J., Gallagher, S., Ossei-Gerning, N., Vardi, G., Baldari, D., Brabham, D., Treasure Ii, C., Dahl, C., Palmer, B., Wiseman, A., Khan, A., Puri, S., Mohart, A. E., Ince, C., Flores, E., Wright, S., Cheng, S., Rosenberg, M., Rogers, W. J., Kosinski, E., Forgosh, L., Waltman, J., Khan, M., Shoukfeh, M., Dagher, G., Cambier, P., Lieber, I., Kumar, P., East, C., Krichmar, P., Hasan, M., White, L., Knickelbine, T., Haldis, T., Gillespie, E., Amidon, T., Suh, D., Arif, I., Abdallah, M., Akhter, F., Carlson, E., D'Urso, M., El-Ahdab, F., Nelson, W., Moriarty, K., Harris, B., Cohen, S., Carter, L., Doty, D., Sabatino, K., Haddad, T., Malik, A., Rao, S., Mulkay, A., Jovin, I., Klancke, K., Malhotra, V., Devarapalli, S. K., Koren, M., Chandna, H., Dodds Iii, G., Goraya, T., Bengston, J., Janik, M., Moran, J., Sumner, A., Kobayashi, J., Davis, W., Yazdani, S., Pasquini, J., Thakkar, M., Vedere, A., Leimbach, W., Rider, J., Fenton, S., Singh, N., Shah, A. V., Janosik, D., Pepine, C., Berman, B., Gelormini, J., Daniels, C., Richard, K., Keating, F., Kondo, N. I., Shetty, S., Levite, H., Waider, W., Takata, T., Abu-Fadel, M., Shah, V., Aggarwal, R., Izzo, M., Kumar, A., Hattler, B., Do, R., Link, C., Bortnick, A., Kinzfogl Iii, G., Ghitis, A., Larry, J., Teufel, E., Kuhlman, P., Mclaurin, B., Zhang, W., Thew, S., Abbas, J., White, M., Islam, O., Subherwal, S., Ranadive, N., Vakili, B., Gring, C., Henderson, D., Schuchard, T., Farhat, N., Kline, G., Mahal, S., Whitaker, J., Speirs, S., Andersen, R., Daboul, N., Horwitz, P., Zahr, F., Ponce, G., Jafar, Z., Mcgarvey, J. J., Panchal, V., Voyce, S., Blok, T., Sheldon, W., Azizad, M. M., Schmalfuss, C., Picone, M., Pederson, R., Herzog, W. J., Friedman, K., Lindsey, J., Nowins, R., Timothy, E., Leonard, P., Lepor, N., El Shahawy, M., Weintraub, H., Irimpen, A., Alonso, A., May, W., Christopher, D., Galski, T., Chu, A., Mody, F., Ramin, E., Hodes, Z., Rossi, J., Rose, G., Fairlamb, J., Lambert, C. J., Raisinghani, A., Abbate, A., Vetrovec, G., King, M., Carey, C., Gerber, J., Younis, L., Park, H. T., Vidovich, M., Knutson, T., Friedman, D., Chaleff, F., Loussararian, A., Rozeman, P., Kimmelstiel, C., Kuvin, J., Silver, K., Foster, M., Tonnessen, G., Espinoza, A., Amlani, M., Wali, A., Malozzi, C., Jong, G. T., Massey, C., Wattanakit, K., O'Donnell, P. J., Singal, D., Jaffrani, N., Banuru, S., Fisher, D., Xenakis, M., Perlmutter, N., Bhagwat, R., Strader, J. J., Blonder, R., Akyea-Djamson, A., Labroo, A., Lee, K., Marais, H. J., Claxton, E. J., Weiss, R., Kathryn, R., Berk, M., Rossi, P., Joshi, P., Khera, A., Khaira, A. S., Kumkumian, G., Lupovitch, S., Purow, J., Welka, S., Hoffman, D., Fischer, S., Soroka, E., Eagerton, D., Pancholy, S., Ray, M., Erenrich, N., Farrar, M., Pollock, S., French, W. J., Diamantis, S., Guy, D., Gimple, L., Neustel, M., Schwartz, S., Pereira, E., Albert, S., Spriggs, D., Strain, J., Mittal, S., Vo, A., Chane, M., Hall, J., Vijay, N., Lotun, K., Lester, F. M., Nahhas, A., Pope, T., Nager, P., Vohra, R., Sharma, M., Bashir, R., Ahmed, H., Berlowitz, M., Fishberg, R., Barrucco, R., Yang, E., Radin, M., Sporn, D., Stapleton, D., Eisenberg, S., Landzberg, J., Mcgough, M., Turk, S., Schwartz, M., Sundram, P. S., Jain, D., Zainea, M., Bayron, C., Karlsberg, R., Dohad, S., Lui, H., Keen, W., Westerhausen, D. J., Khurana, S., Agarwal, H., Birchem, J., Penny, W. J., Chang, M., Murphy, S., Henry, J., Schifferdecker, B., Gilbert, J. M., Chalavarya, G., Eaton, C., Schmedtje, J. F., Christenson, S., Dotani, I., Denham, D., Macdonell, A., Gibson, P., Rahman, A., Al Joundi, T., Assi, N., Conrad, G., Kotha, P., Love, M., Giesler, G., Rubenstein, H., Gamil, D., Akright, L., Krawczyk, J., Cobler, J., Wells, T., Welker, J., Foster, R., Gilmore, R., Anderson, J., Jacoby, D., Harris, B., Gardner, G., Dandillaya, R., Vora, K., Kostis, J., Hunter, J., Laxson, D., Ball, E., Wells, T., Vora, K., Ball, E., Welker, J., Lopes, R., Egydio, F., Kawakami, A., Oliveira, J., Wozniak, J., Matthews, A., Ratky, C., Valiris, J., Berdan, L., Hepditch, A., Quintero, K., Rorick, T., Westbrook, M., Pascual, A., Rovito, C., Bezault, M., Drouet, E., Simon, T., White, H. D., Alsweiler, C., Luyten, A., Butters, J., Griffith, L., Shaw, M., Grunberg, L., Islam, S., Bregeault, M., Bougon, N., Faustino, D., Fontecave, S., Murphy, J., Verrier, M., Agnetti, V., Andersen, D., Badreddine, E., Bekkouche, M., Bouancheau, C., Brigui, I., Brocklehurst, M., Cianciarulo, J., Devaul, D., Domokos, S., Gache, C., Gobillot, C., Guillou, S., Healy, J., Heath, M., Jaiwal, G., Javierre, C., Labeirie, J., Monier, M., Morales, U., Mrabti, A., Mthombeni, B., Okan, B., Smith, L., Sheller, J., Sopena, S., Pellan, V., Benbernou, F., Bengrait, N., Lamoureux, M., Kralova, K., Scemama, M., Bejuit, R., Coulange, A., Berthou, C., Repincay, J., Lorenzato, C., Etienne, A., Gouet, V., Lecorps, G., Loizeau, V., Normand, M., Ourliac, A., Rondel, C., Adamo, A., Beltran, P., Barraud, P., Dubois-Gache, H., Halle, B., Metwally, L., Mourgues, M., Sotty, M., Vincendet, M., Cotruta, R., Chengyue, Z., Fournie-Lloret, D., Morrello, C., Perthuis, A., Picault, P., Zobouyan, I., Colhoun, H. M., Dempsey, M. A., McClanahan, M. A. 2019

    Abstract

    BACKGROUND: After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes.METHODS: ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.FINDINGS: At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (pinteraction=0·11).INTERPRETATION: After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes.FUNDING: Sanofi and Regeneron Pharmaceuticals.

    View details for DOI 10.1016/S2213-8587(19)30158-5

    View details for PubMedID 31272931

  • Polygenic risk scores in coronary artery disease CURRENT OPINION IN CARDIOLOGY Rao, A. S., Knowles, J. W. 2019; 34 (4): 435–40
  • Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017 DIABETOLOGIA Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019; 62 (7): 1185–94
  • No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation DIABETOLOGIA Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019; 62 (5): 800–804
  • Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017. Diabetologia Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019

    Abstract

    AIMS/HYPOTHESIS: The determination of diabetes as underlying cause of death by using the death certificate may result in inaccurate estimation of national mortality attributed to diabetes, because individuals who die with diabetes generally have other conditions that may contribute to their death. We investigated the trends in age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from cardiovascular disease (CVD), complications of diabetes and cancer among individuals with diabetes listed on death certificates in the USA from 2007 to 2017.METHODS: Using the US Census and national mortality database, we calculated age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality rates among adults over 20years with diabetes listed on death certificates. A total of 2,686,590 deaths where diabetes was underlying or contributing cause of death were analysed. We determined temporal mortality rate patterns by joinpoint regression analysis with estimates of annual percentage change (APC).RESULTS: Age-standardised diabetes mortality rates compared among underlying cause of death, contributing cause of death and all-cause mortality were 32.2 vs 75.7 vs 105.1 per 100,000 individuals during the study period. The age-standardised mortality rates due to diabetes as underlying or contributing cause of death declined from 112.2 per 100,000 individuals in 2007 to 104.3 per 100,000 individuals in 2017 with the most pronounced decline noted from 2007 to 2014 (APC -1.4%; 95% CI -1.9%, -1.0%) and stabilisation in decline from 2014 to 2017 (APC 1.1%; 95% CI -0.6%, 2.8%). In terms of cause-specific mortality among individuals with diabetes listed on death certificates, the age-standardised mortality rates for CVD declined at an annual rate of 1.2% with a marked decline of 2.3% between 2007 and 2014. Age-standardised diabetes-specific mortality rates as underlying cause of death decreased from 2007 to 2009 (APC -4.5%) and remained stable from 2009 to 2017. Age-standardised mortality rates for cancer steadily decreased with an average APC of -1.4% (95% CI -1.8%, -1.0%) during the 11-year period. Mortality in the subcategory of CVD demonstrated significant differences.CONCLUSIONS/INTERPRETATION: Current national estimates capture about 30% of all-cause mortality among individuals with diabetes listed as underlying or contributing cause of death on death certificates. The age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from CVD in individuals with diabetes listed as underlying or contributing cause of death plateaued from 2014 onwards except for hypertensive heart disease and heart failure.

    View details for PubMedID 31011776

  • Polygenic risk scores in coronary artery disease. Current opinion in cardiology Rao, A. S., Knowles, J. W. 2019

    Abstract

    PURPOSE OF REVIEW: Large genome-wide association studies (GWAS) have identified variants accounting for a substantial portion of the heritable risk for coronary artery disease (CAD). These studies have not only catalyzed drug discovery but also have opened the possibility of improved risk prediction and stratification. Here we review the current state-of-the art in polygenic risk scores (PRSs) and look to the future, as these scores move towards clinical application.RECENT FINDINGS: Over the last decade, multilocus PRSs for CAD have expanded to include millions of variants and demonstrated strong association with CAD outcomes, even when adjusted for traditional risk factors. Recently, PRSs have shown better prediction of CAD outcomes than any single traditional risk factor alone. Advances in statistical methods used to generate PRSs have improved their predictive ability and transferability between populations with varied ancestries. Initial clinical studies have also demonstrated the potential of genetic information to impact shared decision-making between patients and providers, leading to improved outcomes.SUMMARY: PRSs can improve risk stratification for CAD especially in white/European populations and have the potential to alter routine clinical care. However, unlocking this potential will require additional research in PRSs in nonwhite populations and substantial investment in clinical implementation studies.

    View details for PubMedID 30994529

  • Finding missed cases of familial hypercholesterolemia in health systems using machine learning NPJ DIGITAL MEDICINE Banda, J. M., Sarraju, A., Abbasi, F., Parizo, J., Pariani, M., Ison, H., Briskin, E., Wand, H., Dubois, S., Jung, K., Myers, S. A., Rader, D. J., Leader, J. B., Murray, M. F., Myers, K. D., Wilemon, K., Shah, N. H., Knowles, J. W. 2019; 2
  • Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia DIABETES & VASCULAR DISEASE RESEARCH Raygor, V., Abbasi, F., Lazzeroni, L. C., Kim, S., Ingelsson, E., Reaven, G. M., Knowles, J. W. 2019; 16 (2): 153–59
  • No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation. Diabetologia Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019

    Abstract

    AIMS/HYPOTHESIS: Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach.METHODS: Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA1c on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis.RESULTS: Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p=0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p=0.49) or HbA1c (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p=0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA1c, respectively, for associations with atrial fibrillation.CONCLUSIONS/INTERPRETATION: This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA1c and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention.DATA AVAILABILITY: The datasets analysed during the current study are available from the following repository: Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al (2018) GWAS summary statistics for AF (N=60,620 AF cases and 970,216 controls). Center for Statistical Genetics: http://csg.sph.umich.edu/willer/public/afib2018/nielsen-thorolfsdottir-willer-NG2018-AFib-gwas-summary-statistics.tbl.gz.

    View details for PubMedID 30810766

  • Body composition and atrial fibrillation: a Mendelian randomization study. European heart journal Tikkanen, E., Gustafsson, S., Knowles, J. W., Perez, M., Burgess, S., Ingelsson, E. 2019

    Abstract

    Aims: Increases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF.Methods and results: We conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N=487404, N events=10365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR)=1.77, 95% confidence interval (CI) 1.72-1.83; HR=1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58).Conclusion: Genetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF.

    View details for PubMedID 30721963

  • Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia FRONTIERS IN CARDIOVASCULAR MEDICINE Sarraju, A., Knowles, J. W. 2019; 6
  • Finding missed cases of familial hypercholesterolemia in health systems using machine learning. NPJ digital medicine Banda, J. M., Sarraju, A., Abbasi, F., Parizo, J., Pariani, M., Ison, H., Briskin, E., Wand, H., Dubois, S., Jung, K., Myers, S. A., Rader, D. J., Leader, J. B., Murray, M. F., Myers, K. D., Wilemon, K., Shah, N. H., Knowles, J. W. 2019; 2: 23

    Abstract

    Familial hypercholesterolemia (FH) is an underdiagnosed dominant genetic condition affecting approximately 0.4% of the population and has up to a 20-fold increased risk of coronary artery disease if untreated. Simple screening strategies have false positive rates greater than 95%. As part of the FH Foundation's FIND FH initiative, we developed a classifier to identify potential FH patients using electronic health record (EHR) data at Stanford Health Care. We trained a random forest classifier using data from known patients (n = 197) and matched non-cases (n = 6590). Our classifier obtained a positive predictive value (PPV) of 0.88 and sensitivity of 0.75 on a held-out test-set. We evaluated the accuracy of the classifier's predictions by chart review of 100 patients at risk of FH not included in the original dataset. The classifier correctly flagged 84% of patients at the highest probability threshold, with decreasing performance as the threshold lowers. In external validation on 466 FH patients (236 with genetically proven FH) and 5000 matched non-cases from the Geisinger Healthcare System our FH classifier achieved a PPV of 0.85. Our EHR-derived FH classifier is effective in finding candidate patients for further FH screening. Such machine learning guided strategies can lead to effective identification of the highest risk patients for enhanced management strategies.

    View details for DOI 10.1038/s41746-019-0101-5

    View details for PubMedID 31304370

    View details for PubMedCentralID PMC6550268

  • Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia. Frontiers in cardiovascular medicine Sarraju, A., Knowles, J. W. 2019; 6: 5

    Abstract

    Familial Hypercholesterolemia (FH) is an inherited lipid disorder affecting 1 in 220 individuals resulting in highly elevated low-density lipoprotein levels and risk of premature coronary disease. Pathogenic variants causing FH typically involve the LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtulisin/kexin type 9 genes (PCSK9) and if identified convey a risk of early onset coronary artery disease (ASCVD) of 3- to 10-fold vs. the general population depending on the severity of the mutation. Identification of monogenic FH within a family has implications for family-based testing (cascade screening), risk stratification, and potentially management, and it has now been recommended that such testing be offered to all potential FH patients. Recently, robust genome wide association studies (GWAS) have led to the recognition that the accumulation of common, small effect alleles affecting many LDL-c raising genes can result in a clinical phenotype largely indistinguishable from monogenic FH (i.e., a risk of early onset ASCVD of ~3-fold) in those at the extreme tail of the distribution for these alleles (i.e., the top 8% of the population for a polygenic risk score). The incorporation of these genetic risk scores into clinical practice for non-FH patients may improve risk stratification but is not yet widely performed due to a less robust evidence base for utility. Here, we review the current status of FH genetic testing, potential future applications as well as challenges and pitfalls.

    View details for PubMedID 30761309

  • Association of Statin Adherence With Mortality in Patients With Atherosclerotic Cardiovascular Disease. JAMA cardiology Rodriguez, F., Maron, D. J., Knowles, J. W., Virani, S. S., Lin, S., Heidenreich, P. A. 2019

    Abstract

    Statins decrease mortality in those with atherosclerotic cardiovascular disease (ASCVD), but statin adherence remains suboptimal.To determine the association between statin adherence and mortality in patients with ASCVD who have stable statin prescriptions.This retrospective cohort analysis included patients who were between ages 21 and 85 years and had 1 or more International Classification of Diseases, Ninth Revision, Clinical Modification codes for ASCVD on 2 or more dates in the previous 2 years without intensity changes to their statin prescription who were treated within the Veterans Affairs Health System between January 1, 2013, and April 2014.Statin adherence was defined by the medication possession ratio (MPR). Adherence levels were categorized as an MPR of less than 50%, 50% to 69%, 70% to 89%, and 90% or greater. For dichotomous analyses, adherence was defined as an MPR of 80% or greater.The primary outcome was death of all causes adjusted for demographic and clinical characteristics, as well as adherence to other cardiac medications.Of 347 104 eligible adults with ASCVD who had stable statin prescriptions, 5472 (1.6%) were women, 284 150 (81.9%) were white, 36 208 (10.4%) were African American, 16 323 (4.7%) were Hispanic, 4093 (1.2%) were Pacific Islander, 1293 (0.4%) were Native American, 1145 (0.3%) were Asian, and 1794 (0.5%) were other races. Patients taking moderate-intensity statin therapy were more adherent than patients taking high-intensity statin therapy (odds ratio [OR], 1.18; 95% CI, 1.16-1.20). Women were less adherent (OR, 0.89; 95% CI, 0.84-0.94), as were minority groups. Younger and older patients were less likely to be adherent compared with adults aged 65 to 74 years. During a mean (SD) of 2.9 (0.8) years of follow-up, there were 85 930 deaths (24.8%). Compared with the most adherent patients (MPR ≥ 90%), patients with an MPR of less than 50% had a hazard ratio (HR; adjusted for clinical characteristics and adherence to other cardiac medications) of 1.30 (95% CI, 1.27-1.34), those with an MPR of 50% to 69% had an HR of 1.21 (95% CI, 1.18-1.24), and those with an MPR of 70% to 89% had an HR of 1.08 (95% CI, 1.06-1.09).Using a national sample of Veterans Affairs patients with ASCVD, we found that a low adherence to statin therapy was associated with a greater risk of dying. Women, minorities, younger adults, and older adults were less likely to adhere to statins. Our findings underscore the importance of finding methods to improve adherence.

    View details for PubMedID 30758506

  • Safety and Efficacy of PCSK9 Inhibitors After Heart Transplantation. The Canadian journal of cardiology Moayedi, Y., Kozuszko, S., Knowles, J. W., Chih, S., Oro, G., Lee, R., Fearon, W. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2019; 35 (1)

    Abstract

    Dyslipidemia is common in patients undergoing heart transplantation and is associated with the progression of cardiac allograft vasculopathy. Two monoclonal antibodies directed against PCSK9i-evolocumab and alirocumab-are currently available. However, their use, safety and efficacy in the post-transplant setting have not been studied. We present our experience with 6 heart transplant recipients treated with a PCSK9i. A > 70% reduction in LDL-cholesterol was observed after evolocumab therapy. PCSK9 inhibitors are a potentially lipid-lowering therapeutic option for heart transplant patients with suboptimal LDL despite maximal tolerated statin doses.

    View details for PubMedID 30595172

  • Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia. Diabetes & vascular disease research Raygor, V., Abbasi, F., Lazzeroni, L. C., Kim, S., Ingelsson, E., Reaven, G. M., Knowles, J. W. 2019; 16 (2): 153–59

    Abstract

    Insulin sensitivity affects plasma triglyceride concentration and both differ by race/ethnicity. The purpose of this study was to provide a comprehensive assessment of the variation in insulin sensitivity and its relationship to hypertriglyceridaemia between five race/ethnic groups.In this cross-sectional study, clinical data for 1025 healthy non-Hispanic White, Hispanic White, East Asian, South Asian and African American individuals were analysed. Insulin-mediated glucose disposal (a direct measure of peripheral insulin sensitivity) was measured using the modified insulin suppression test. Statistical analysis was performed using analysis of co-variance.Of the study participants, 63% were non-Hispanic White, 9% were Hispanic White, 11% were East Asian, 11% were South Asian and 6% were African American. Overall, non-Hispanic Whites and African Americans displayed greater insulin sensitivity than East Asians and South Asians. Triglyceride concentration was positively associated with insulin resistance in all groups, including African Americans. Nevertheless, for any given level of insulin sensitivity, African Americans had the lowest triglyceride concentrations.Insulin sensitivity, as assessed by a direct measure of insulin-mediated glucose disposal, and its relationship to triglyceride concentration vary across five race/ethnic groups. Understanding these relationships is crucial for accurate cardiovascular risk stratification and prevention.

    View details for PubMedID 31014093

  • Increasing Mortality Among Patients With Diabetes and Chronic Liver Disease From 2007 Through 2017. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Kim, D., Cholankeril, G., Kim, S. H., Abbasi, F., Knowles, J. W., Ahmed, A. 2019

    View details for DOI 10.1016/j.cgh.2019.06.011

    View details for PubMedID 31220638

  • ClinVar database of global familial hypercholesterolemia-associated DNA variants. Human mutation Iacocca, M. A., Chora, J. R., Carrie, A., Freiberger, T., Leigh, S. E., Defesche, J. C., Kurtz, C. L., DiStefano, M. T., Santos, R. D., Humphries, S. E., Mata, P., Jannes, C. E., Hooper, A. J., Wilemon, K. A., Benlian, P., O'Connor, R., Garcia, J., Wand, H., Tichy, L., Sijbrands, E. J., Hegele, R. A., Bourbon, M., Knowles, J. W., ClinGen FH Variant Curation Expert Panel 2018; 39 (11): 1631–40

    Abstract

    Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.

    View details for PubMedID 30311388

  • Genome-wide scan for circulating vascular adhesion protein-1 levels: MACROD2 as a potential transcriptional regulator of adipogenesis JOURNAL OF DIABETES INVESTIGATION Chang, Y., Hee, S., Lee, W., Li, H., Chang, T., Lin, M., Hung, Y., Lee, I., Hung, K., Assimes, T., Knowles, J. W., Nong, J., Lee, P., Chiu, Y., Chuang, L. 2018; 9 (5): 1067–74

    Abstract

    Vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP-1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP-1 levels.We carried out a genomic-wide linkage scan for the quantitative trait locus of circulating VAP-1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single-nucleotide polymorphisms.The estimated heritability of circulating VAP-1 levels is high (h2 = 69%). The most significant quantitative trait locus for circulating VAP-1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 (P = 6.86 × 10-6 ) in females. Regional single-nucleotide polymorphism fine mapping within a 1-unit support region showed the strongest association signals in the MACRO domain containing 2 (MACROD2) gene in females (P = 5.38 × 10-6 ). Knockdown of MACROD2 significantly suppressed VAP-1 expression in human adipocytes, as well as the expression of key adipogenic genes. Furthermore, MACROD2 expression was found to be positively associated with VAP-1 in human visceral adipose tissue.MACROD2 is a potential genetic determinant of serum VAP-1 levels, probably through transcriptional regulation of adipogenesis.

    View details for PubMedID 29364582

  • Clinical Genetic Testing for Familial Hypercholesterolemia JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Sturm, A. C., Knowles, J. W., Gidding, S. S., Ahmad, Z. S., Ahmed, C. D., Ballantyne, C. M., Baum, S. J., Bourbon, M., Carrie, A., Cuchel, M., de Ferranti, S. D., Defesche, J. C., Freiberger, T., Hershberger, R. E., Hovingh, G., Karayan, L., Kastelein, J., Kindt, I., Lane, S. R., Leigh, S. E., Linton, M. F., Mata, P., Neal, W. A., Nordestgaard, B. G., Santos, R. D., Harada-Shiba, M., Sijbrands, E. J., Stitziel, N. O., Yamashita, S., Wilemon, K. A., Ledbetter, D. H., Rader, D. J., Familial Hypercholesterolemia Fdn 2018; 72 (6): 662–80

    Abstract

    Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.

    View details for PubMedID 30071997

  • Large-Scale Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection Against Ischemic Stroke CIRCULATION-GENOMIC AND PRECISION MEDICINE Rao, A. S., Lindholm, D., Rivas, M. A., Knowles, J. W., Montgomery, S. B., Ingelsson, E. 2018; 11 (7): e002162

    Abstract

    PCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes.We tested the association of the PCSK9 missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of PCSK9 inhibition with higher power at a finer resolution.The T allele of rs11591147 showed a protective effect on hyperlipidemia (odds ratio, 0.63±0.04; P=2.32×10-38), coronary heart disease (odds ratio, 0.73±0.09; P=1.05×10-6), and ischemic stroke (odds ratio, 0.61±0.18; P=2.40×10-3) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24±0.10; P=1.98×10-7). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct PCSK9 inhibition; off-target effects cannot be predicted using this approach.This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to LDL (low-density lipoprotein) cholesterol, atherosclerosis, and type 2 diabetes mellitus, suggesting that other effects are either small or absent.

    View details for PubMedID 29997226

  • Frequency of Statin Use in Patients With Low-Density Lipoprotein Cholesterol ≥190 mg/dl from the Veterans Affairs Health System. The American journal of cardiology Rodriguez, F., Knowles, J. W., Maron, D. J., Virani, S. S., Heidenreich, P. A. 2018

    Abstract

    Patients with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dl have severe hypercholesterolemia and are at markedly increased risk for adverse cardiovascular events. This study sought to examine the prevalence and treatment of patients with uncontrolled severe hypercholesterolemia in the Veterans Affairs (VA) Health System. The study population was comprised of VA outpatients ≥21 years of age without atherosclerotic disease or diabetes mellitus and an index LDL-C ≥190 mg/dl during April 2011 to March 2014. Patients needed to have filled medications at the VA within the past 6 months. Patient and facility-level predictors of statin use, high-intensity statin use, and statin intensification were analyzed using multivariate logistic regressions. There were a total of 63,576 patients meeting inclusion criteria, including 8,553 (13.5%) women and 26,879 (29.0%) nonwhite patients. The mean (±S.D.) age was 55 (±13) years and the mean of the most recent LDL-C values was 207 ± 22 mg/dl. Only 52% of all eligible patients were on any statin therapy and 9.7% received high-intensity statin therapy. High-intensity statin use increased from 8.6% in 2011 to 13.6% in 2014 (p < 0.001). In adjusted analysis, patients <35 or >75 years of age were less likely to be on a statin (p < 0.001). Women were less likely to be treated than men, odds ratio = 0.88; 95% confidence interval (0.83, 0.92). Similar patterns were observed for predictors of high-intensity statin use and statin intensification. In conclusion, only half of high-risk VA patients with uncontrolled severe hypercholesterolemia were treated with statins and a small minority was on high-intensity statin therapy.

    View details for PubMedID 30055758

  • Short-Term Repeatability of Insulin Resistance Indexes in Older Adults: The Atherosclerosis Risk in Communities Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Poon, A. K., Meyer, M. L., Reaven, G., Knowles, J. W., Selvin, E., Pankow, J. S., Couper, D., Loehr, L., Heiss, G. 2018; 103 (6): 2175–81

    Abstract

    The homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) are insulin resistance indexes routinely used in clinical and population-based studies; however, their short-term repeatability is not well characterized.To quantify the short-term repeatability of insulin resistance indexes and their analytes, consisting of fasting glucose and insulin for HOMA-IR and TG and HDL-C for TG/HDL-C.Prospective cohort study.A total of 102 adults 68 to 88 years old without diabetes attended an initial examination and repeated examination (mean, 46 days; range, 28 to 102 days). Blood samples were collected, processed, shipped, and assayed following a standardized protocol.Repeatability was quantified using the intraclass correlation coefficient (ICC) and within-person coefficient of variation (CV). Minimum detectable change (MDC95) and minimum detectable difference with 95% confidence (MDD95) were quantified.For HOMA-IR, insulin, and fasting glucose, the ICCs were 0.70, 0.68, and 0.70, respectively; their respective within-person CVs were 30.4%, 28.8%, and 5.6%. For TG/HDL-C, TG, and HDL-C, the ICCs were 0.80, 0.68, and 0.91, respectively; their respective within-person CVs were 23.0%, 20.6%, and 8.2%. The MDC95 was 2.3 for HOMA-IR and 1.4 for TG/HDL-C. The MDD95 for a sample of n = 100 was 0.8 for HOMA-IR and 0.6 for TG/HDL-C.Short-term repeatability was fair to good for HOMA-IR and excellent for TG/HDL-C according to suggested benchmarks, reflecting the short-term variability of their analytes. These measurement properties can inform the use of these indexes in clinical and population-based studies.

    View details for PubMedID 29618016

  • ADAPTATION OF ACMG/AMP GUIDELINES FOR STANDARDIZED VARIANT INTERPRETATION IN FAMILIAL HYPERCHOLESTEROLEMIA Iacocca, M. A., Chora, J., Carrie, A., Leigh, S. E., Tichy, L., DiStefano, M. T., Defesche, J., Kurtz, C. L., Sijbrands, E. J., Freiberger, T., Hegele, R. A., Knowles, J. W., Bourbon, M. ELSEVIER IRELAND LTD. 2018: 51
  • Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes. Heart (British Cardiac Society) Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018

    Abstract

    OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM).METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings.RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+Swave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69mV vs 0.21±0.17mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (rho=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity.CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

    View details for PubMedID 29680808

  • Cardiovascular disease: The rise of the genetic risk score PLOS MEDICINE Knowles, J. W., Ashley, E. A. 2018; 15 (3): e1002546

    Abstract

    In a Perspective, Joshua Knowles and Euan Ashley discuss the potential for use of genetic risk scores in clinical practice.

    View details for PubMedID 29601582

  • First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring. The Journal of pediatrics Helle, E. I., Biegley, P., Knowles, J. W., Leader, J. B., Pendergrass, S., Yang, W., Reaven, G. R., Shaw, G. M., Ritchie, M., Priest, J. R. 2018; 195: 275–78

    Abstract

    In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.

    View details for PubMedID 29254757

    View details for PubMedCentralID PMC5869072

  • Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH (TM) patient registry ATHEROSCLEROSIS Amrock, S. M., Duell, P., Knickelbine, T., Martin, S. S., O'Brien, E. C., Watson, K. E., Mitri, J., Kindt, I., Shrader, P., Baum, S. J., Hemphill, L. C., Ahmed, C. D., Andersen, R. L., Kullo, I. J., McCann, D., Larry, J. A., Murray, M. F., Fishberg, R., Guyton, J. R., Wilemon, K., Roe, M. T., Rader, D. J., Ballantyne, C. M., Underberg, J. A., Thompson, P., Duffy, D., Linton, M. F., Shapiro, M. D., Moriarty, P. M., Knowles, J. W., Ahmad, Z. S. 2017; 267: 19–26

    Abstract

    Most familial hypercholesterolemia (FH) patients remain undertreated, and it is unclear what role health disparities may play for FH patients in the US. We sought to describe sex and racial/ethnic disparities in a national registry of US FH patients.We analyzed data from 3167 adults enrolled in the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) registry. Logistic regression was used to evaluate for disparities in LDL-C goals and statin use, with adjustments for covariates including age, cardiovascular risk factors, and statin intolerance.In adjusted analyses, women were less likely than men to achieve treated LDL-C of <100 mg/dL (OR 0.68, 95% CI, 0.57-0.82) or ≥50% reduction from pretreatment LDL-C (OR 0.79, 95% CI, 0.65-0.96). Women were less likely than men to receive statin therapy (OR, 0.60, 95% CI, 0.50-0.73) and less likely to receive a high-intensity statin (OR, 0.60, 95% CI, 0.49-0.72). LDL-C goal achievement also varied by race/ethnicity: compared with whites, Asians and blacks were less likely to achieve LDL-C levels <100 mg/dL (Asians, OR, 0.47, 95% CI, 0.24-0.94; blacks, OR, 0.49, 95% CI, 0.32-0.74) or ≥50% reduction from pretreatment LDL-C (Asians, OR 0.56, 95% CI, 0.32-0.98; blacks, OR 0.62, 95% CI, 0.43-0.90).In a contemporary US population of FH patients, we identified differences in LDL-C goal attainment and statin usage after stratifying the population by either sex or race/ethnicity. Our findings suggest that health disparities contribute to the undertreatment of US FH patients. Increased efforts are warranted to raise awareness of these disparities.

    View details for PubMedID 29080546

  • Relationship between simple markers of insulin resistance and coronary artery calcification JOURNAL OF CLINICAL LIPIDOLOGY Reaven, G. M., Knowles, J. W., Leonard, D., Barlow, C. E., Willis, B. L., Haskell, W. L., Maron, D. J. 2017; 11 (4): 1007–12

    Abstract

    Insulin resistance in apparently healthy persons is associated with a cluster of metabolic abnormalities that promote coronary atherosclerosis. Identifying these individuals before manifest disease would provide useful clinical information.We hypothesized that combining 2 simple markers of insulin resistance, prediabetes (PreDM) and triglyceride (TG) concentration ≥150 mg/dL, would identify apparently healthy persons with adverse cardiometabolic risk profiles and increased coronary artery calcium (CAC) compared with those with neither or only 1 abnormality.A cross-sectional analysis was performed using data from 25,886 apparently healthy individuals (18,453 men and 7433 women) evaluated at the Cooper Clinic from 1998 to 2015. Participants were divided into those with a normal fasting glucose concentrations (<100 mg/dL = normal fasting glucose) or PreDM (fasting plasma glucose ≥100 and <126 mg/dL) and further subdivided into those with a plasma TG concentration <150 or ≥150 mg/dL. These 4 groups were compared on the basis of multiple coronary artery disease risk factors and the presence of CAC determined during their evaluation.Participants with PreDM and a TG concentration ≥150 mg/dL had a significantly more adverse coronary artery disease risk profile than individuals with either abnormality or only 1 abnormality (PreDM or TG concentration ≥150 mg/dL). Furthermore, the odds of detectable CAC were higher in participants with PreDM and a TG ≥ 150 mg/dL than in participants with neither or only 1 abnormality.The presence of 2 markers of insulin resistance, PreDM and TG concentration ≥150 mg/dL, is associated with increased cardiometabolic risk and detectable CAC within a population of apparently healthy individuals.

    View details for PubMedID 28652190

  • Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Knowles, J. W., Rader, D. J., Khoury, M. J. 2017; 318 (4): 381–82

    View details for PubMedID 28742895

    View details for PubMedCentralID PMC6166431

  • Access to Nonstatin Lipid-Lowering Therapies in Patients at High Risk of Atherosclerotic Cardiovascular Disease CIRCULATION Knowles, J. W., Howard, W. B., Karayan, L., Baum, S. J., Wilemon, K. A., Ballantyne, C. M., Myers, K. D. 2017; 135 (22): 2204–6

    View details for PubMedID 28446516

  • Leveraging Human Genetics to Understand the Relation of LDL Cholesterol with Type 2 Diabetes. Clinical chemistry Ingelsson, E., Knowles, J. W. 2017

    View details for DOI 10.1373/clinchem.2016.268565

    View details for PubMedID 28515096

  • Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity CELL STEM CELL Carcamo-Orive, I., Hoffman, G. E., Cundiff, P., Beckmann, N. D., D'Souza, S. L., Knowles, J. W., Patel, A., Papatsenko, D., Abbasi, F., Reaven, G. M., Whalen, S., Lee, P., Shahbazi, M., Henrion, M. Y., Zhu, K., Wang, S., Roussos, P., Schadt, E. E., Pandey, G., Chang, R., Quertermous, T., Lemischka, I. 2017; 20 (4): 518-?

    Abstract

    Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ∼50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern. Network, pathway, and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications.

    View details for DOI 10.1016/j.stem.2016.11.005

    View details for Web of Science ID 000398350800015

    View details for PubMedCentralID PMC5384872

  • The role of registries and genetic databases in familial hypercholesterolemia. Current opinion in lipidology Kindt, I., Mata, P., Knowles, J. W. 2017; 28 (2): 152-160

    Abstract

    To review how leveraging familial hypercholesterolemia registries can impact molecular genetic research and precision medicine.Familial hypercholesterolemia is both much more common and more phenotypically heterogeneous than previously thought with some evidence for significant genotype to phenotype correlations. Genetic testing for familial hypercholesterolemia is becoming both more widely available and cheaper, spurring conversations about its clinical utility.In most countries, familial hypercholesterolemia is underdiagnosed and diagnosed later in life, often after the onset of coronary heart disease (CHD). Familial hypercholesterolemia is undertreated; low goal attainment and additional modifiable risk factors further increase CHD risk. Familial hypercholesterolemia epitomizes the goal of precision medicine to define a subset of individuals with a high risk of morbidity and mortality through genetic diagnosis to manage and treat the risk accordingly. Genetic cascade screening can be used to identify familial hypercholesterolemia patients at a younger age and start timely treatment to prevent CHD. Familial hypercholesterolemia registries are tools for clinical research and improving healthcare planning and patient care. As genotype and phenotype correlations in familial hypercholesterolemia become increasingly understood, this information will likely play a more important role in diagnosis and treatment especially as the cost of genetic testing continues to decline.

    View details for DOI 10.1097/MOL.0000000000000398

    View details for PubMedID 28169870

  • PREDICTORS OF STATIN USE FOR PATIENTS WITH LDL CHOLESTEROL ABOVE 190MG/DL: INSIGHTS FROM THE VETERANS AFFAIRS HEALTH CARE SYSTEM Rodriguez, F., Knowles, J., Maron, D., Virani, S., Heidenreich, P. ELSEVIER SCIENCE INC. 2017: 1693
  • Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome. Arteriosclerosis, thrombosis, and vascular biology Carcamo-Orive, I., Huang, N. F., Quertermous, T., Knowles, J. W. 2017; 37 (11): 2038–42

    Abstract

    Insulin resistance leads to a number of metabolic and cellular abnormalities including endothelial dysfunction that increase the risk of vascular disease. Although it has been particularly challenging to study the genetic determinants that predispose to abnormal function of the endothelium in insulin-resistant states, the possibility of deriving endothelial cells from induced pluripotent stem cells generated from individuals with detailed clinical phenotyping, including accurate measurements of insulin resistance accompanied by multilevel omic data (eg, genetic and genomic characterization), has opened new avenues to study this relationship. Unfortunately, several technical barriers have hampered these efforts. In the present review, we summarize the current status of induced pluripotent stem cell-derived endothelial cells for modeling endothelial dysfunction associated with insulin resistance and discuss the challenges to overcoming these limitations.

    View details for PubMedID 28729365

    View details for PubMedCentralID PMC5669062

  • Is ACS in Young Patients a "Canary in the Coal Mine" for Familial Hypercholesterolemia? Journal of the American College of Cardiology Knowles, J. W., Sarraju, A. 2017; 70 (14): 1741–43

    View details for PubMedID 28958331

  • Association Between Intensity of Statin Therapy and Mortality in Patients With Atherosclerotic Cardiovascular Disease. JAMA cardiology Rodriguez, F., Maron, D. J., Knowles, J. W., Virani, S. S., Lin, S., Heidenreich, P. A. 2017; 2 (1): 47-54

    Abstract

    High-intensity statin therapy is recommended for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Nevertheless, statin therapy in general, and high-intensity statin therapy in particular, is underused in patients with established ASCVD.To determine the association between all-cause mortality and intensity of statin therapy in the Veterans Affairs health care system.A retrospective cohort analysis was conducted of patients aged 21 to 84 years with ASCVD treated in the Veterans Affairs health care system from April 1, 2013, to April 1, 2014. Patients who were included had 1 or more International Classification of Diseases, Ninth Revision codes for ASCVD on 2 or more different dates in the prior 2 years.Intensity of statin therapy was defined by the 2013 American College of Cardiology/American Heart Association guidelines, and use was defined as a filled prescription in the prior 6 months. Patients were excluded if they were taking a higher statin dose in the prior 5 years.The primary outcome was death from all causes adjusted for the propensity to receive high-intensity statins.The study sample included 509 766 eligible adults with ASCVD at baseline (mean [SD] age, 68.5 [8.8] years; 499 598 men and 10 168 women), including 150 928 (29.6%) receiving high-intensity statin therapy, 232 293 (45.6%) receiving moderate-intensity statin therapy, 33 920 (6.7%) receiving low-intensity statin therapy, and 92 625 (18.2%) receiving no statins. During a mean follow-up of 492 days, there was a graded association between intensity of statin therapy and mortality, with 1-year mortality rates of 4.0% (5103 of 126 139) for those receiving high-intensity statin therapy, 4.8% (9703 of 200 709) for those receiving moderate-intensity statin therapy, 5.7% (1632 of 28 765) for those receiving low-intensity statin therapy, and 6.6% (4868 of 73 728) for those receiving no statin (P < .001). After adjusting for the propensity to receive high-intensity statins, the hazard ratio for mortality was 0.91 (95% CI, 0.88-0.93) for those receiving high- vs moderate-intensity statins. The magnitude of benefit of high- vs moderate-intensity statins was similar, for an incident cohort hazard ratio of 0.93 (95% CI, 0.85-1.01). For patients aged 76 to 84 years, the hazard ratio was 0.91 (95% CI, 0.87-0.95). Patients treated with maximal doses of high-intensity statins had lower mortality (hazard ratio, 0.90; 95% CI, 0.87-0.94) compared with those receiving submaximal doses.We found a graded association between intensity of statin therapy and mortality in a national sample of patients with ASCVD. High-intensity statins were associated with a small but significant survival advantage compared with moderate-intensity statins, even among older adults. Maximal doses of high-intensity statins were associated with a further survival benefit.

    View details for DOI 10.1001/jamacardio.2016.4052

    View details for PubMedID 27829091

  • Impact of a Genetic Risk Score for Coronary Artery Disease on Reducing Cardiovascular Risk: A Pilot Randomized Controlled Study. Frontiers in cardiovascular medicine Knowles, J. W., Zarafshar, S., Pavlovic, A., Goldstein, B. A., Tsai, S., Li, J., McConnell, M. V., Absher, D., Ashley, E. A., Kiernan, M., Ioannidis, J. P., Assimes, T. L. 2017; 4: 53

    Abstract

    We tested whether providing a genetic risk score (GRS) for coronary artery disease (CAD) would serve as a motivator to improve adherence to risk-reducing strategies.We randomized 94 participants with at least moderate risk of CAD to receive standard-of-care with (N = 49) or without (N = 45) their GRS at a subsequent 3-month follow-up visit. Our primary outcome was change in low density lipoprotein cholesterol (LDL-C) between the 3- and 6-month follow-up visits (ΔLDL-C). Secondary outcomes included other CAD risk factors, weight loss, diet, physical activity, risk perceptions, and psychological outcomes. In pre-specified analyses, we examined whether there was a greater motivational effect in participants with a higher GRS.Sixty-five participants completed the protocol including 30 participants in the GRS arm. We found no change in the primary outcome between participants receiving their GRS and standard-of-care participants (ΔLDL-C: -13 vs. -9 mg/dl). Among participants with a higher GRS, we observed modest effects on weight loss and physical activity. All other secondary outcomes were not significantly different, including anxiety and worry.Adding GRS to standard-of-care did not change lipids, adherence, or psychological outcomes. Potential modest benefits in weight loss and physical activity for participants with high GRS need to be validated in larger trials.

    View details for PubMedID 28856136

  • Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity. Cell stem cell Carcamo-Orive, I., Hoffman, G. E., Cundiff, P., Beckmann, N. D., D'Souza, S. L., Knowles, J. W., Patel, A., Papatsenko, D., Abbasi, F., Reaven, G. M., Whalen, S., Lee, P., Shahbazi, M., Henrion, M. Y., Zhu, K., Wang, S., Roussos, P., Schadt, E. E., Pandey, G., Chang, R., Quertermous, T., Lemischka, I. 2016

    Abstract

    Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ∼50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern. Network, pathway, and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications.

    View details for DOI 10.1016/j.stem.2016.11.005

    View details for PubMedID 28017796

  • Use of high-intensity statins for patients with atherosclerotic cardiovascular disease in the Veterans Affairs Health System: Practice impact of the new cholesterol guidelines AMERICAN HEART JOURNAL Rodriguez, F., Lin, S., Maron, D. J., Knowles, J. W., Virani, S. S., Heidenreich, P. A. 2016; 182: 97-102

    Abstract

    The November 2013 American College of Cardiology/American Heart Association cholesterol guidelines recommend the use of high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). We sought to determine how these guidelines are being adopted at the Veterans Affairs (VA) Health System and identify treatment gaps.We examined administrative data from the VA 12 months prior to the index dates of April 1, 2013, and after April 1, 2014, to identify patients ≤75 years of age with ≥2 codes for ASCVD. We identified those on high-intensity statin therapy (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, and simvastatin 80 mg) during the 6 months after the index date.The study sample included 331,927 and 326,759 eligible adults with ASCVD before and after the release of the new guidelines, respectively. Overall, high-intensity statin use increased from 28% to 35% after guideline release. High-intensity statin use was lowest in Hispanics and Native Americans, although all groups showed an increase over time. Among those on low- or moderate-intensity statin therapy, 15.6% were intensified to a high-intensity statin after guideline release. Groups less likely to undergo statin intensification were older adults (odds ratio=0.78 for each 10-year increase, 95% CI 0.76-0.81), women (odds ratio=0.86, 95% CI 0.75-0.99), and certain minority groups. Academic teaching hospitals and hospitals on the West Coast were more likely to intensify statins after release of the new guidelines.High-intensity statin use increased in the VA following release of the American College of Cardiology/American Heart Association cholesterol treatment guidelines, although disparities persist for certain patient groups including older adults, women, and certain minority groups.

    View details for DOI 10.1016/j.ahj.2016.09.007

    View details for Web of Science ID 000389136600012

    View details for PubMedID 27914506

  • Novel Therapies for Familial Hypercholesterolemia. Current treatment options in cardiovascular medicine Parizo, J., Sarraju, A., Knowles, J. W. 2016; 18 (11): 64-?

    Abstract

    Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50 %. The LDL-C target is adjusted to <100 or <70 mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added. Finally, LDL-C apheresis can be considered in patients with LDL-C >300 mg/dL (or >200 mg/dL with significant CAD, although now approved for LDL-C as low as 160 mg/dL with CAD). Due to the early, severe LDL-C elevation in HoFH patients, concerning natural history, rarity of the condition, and nuances of treatment, all HoFH patients should be treated at a pediatric or adult center with HoFH experience. LDL-C apheresis should be considered as early as 5 years of age. However, apheresis availability and tolerability is limited and pharmacotherapy is required. Generally, the AHA algorithm with reference to the European Atherosclerosis Society Consensus Panel recommendations is reasonable with all patients initiated on high-dose, high-potency statin, ezetimibe, and bile acid-binding resins. In most, additional LDL-C lowering is required with PCSK9 inhibitors and/or lomitapide or mipomersen. Liver transplantation can also be considered at experienced centers as a last resort.

    View details for DOI 10.1007/s11936-016-0486-2

    View details for PubMedID 27620638

  • Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials). American journal of cardiology Kohli, P., Knowles, J. W., Sarraju, A., Waters, D. D., Reaven, G. 2016; 118 (9): 1275-1281

    Abstract

    The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m(2)), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m(2) <27.0 and ≥27.0) for TG concentrations. Patients received atorvastatin or placebo for a median duration of 4.9 years. Incident T2DM, defined by developing at least 2 fasting plasma glucose (FPG) concentrations ≥126 mg/dl, an increase in FPG ≥37 mg/dl, or a clinical diagnosis of T2DM, was observed in 8.2% of the total population. T2DM event rates (statin or placebo) varied from a low of 2.8%/3.2% (NFG and TG ≤1.7 mmol/l) to a high of 22.8%/7.6% (PreDM and TG >1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.

    View details for DOI 10.1016/j.amjcard.2016.07.054

    View details for PubMedID 27614854

  • Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice CELL REPORTS Chennamsetty, I., Coronado, M., Contrepois, K., Keller, M. P., Carcamo-Orive, I., Sandin, J., Fajardo, G., Whittle, A. J., Fathzadeh, M., Snyder, M., Reaven, G., Attie, A. D., Bernstein, D., Quertermous, T., Knowles, J. W. 2016; 17 (2): 527-540

    Abstract

    We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here, we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key mitochondrial genes. RNAi-mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration, and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts, and in tissues from Nat1-deficient mice, including white adipose tissue, heart, and skeletal muscle. Nat1-deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.

    View details for DOI 10.1016/j.celrep.2016.09.005

    View details for Web of Science ID 000385850700019

    View details for PubMedID 27705799

    View details for PubMedCentralID PMC5097870

  • Hypertriglyceridemia: A simple approach to identify insulin resistance and enhanced cardio-metabolic risk in patients with prediabetes. Diabetes research and clinical practice Abbasi, F., Kohli, P., Reaven, G. M., Knowles, J. W. 2016; 120: 156-161

    Abstract

    Prediabetes (PreDM) is a metabolically heterogeneous condition, differing in degree of insulin resistance and risk of type 2 diabetes mellitus and coronary heart disease (CHD). This study was initiated to evaluate the hypothesis that a fasting plasma triglyceride (TG) concentration ⩾1.7mmol/L can aid in identifying the subset of individuals with PreDM who are most insulin resistant and at greatest risk to develop CHD as well as type 2 diabetes mellitus.In this cross-sectional study, measurements were made of: (1) steady-state plasma glucose (SSPG) concentration during the insulin suppression test to ascertain degree of insulin resistance and (2) conventional CHD risk factors in 587 apparently healthy individuals with normal fasting plasma glucose (NFG, n=370) or PreDM (n=217).Subjects with PreDM were significantly (P<0.001) more insulin resistant (higher SSPG concentrations) and had a more adverse CHD risk profile than those with NFG. A TG concentration ⩾1.7mmol/L identified a subset of individuals with PreDM (38%) who had a higher mean SSPG concentration (11.3±3.5mmol/L vs. 9.3±3.9mmol/L, P<0.001), were more likely to be insulin resistant (66% vs. 39%, P<0.001), and had a more adverse CHD risk factor profile.Measurement of fasting TG concentration in individuals with PreDM may provide a simple clinical approach to identify those who are insulin resistant, at enhanced risk of CHD, and more likely to develop type 2 diabetes mellitus.

    View details for DOI 10.1016/j.diabres.2016.07.024

    View details for PubMedID 27565692

  • US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry JOURNAL OF CLINICAL LIPIDOLOGY Ahmad, Z. S., Andersen, R. L., Andersen, L. H., O'Brien, E. C., Kindt, I., Shrader, P., Vasandani, C., Newman, C. B., DeGoma, E. M., Baum, S. J., Hemphill, L. C., Hudgins, L. C., Ahmed, C. D., Kullo, I. J., Gidding, S. S., Duffy, D., Neal, W., Wilemon, K., Roe, M. T., Rader, D. J., Ballantyne, C. M., Linton, M. F., Duell, P. B., Shapiro, M. D., Moriarty, P. M., Knowles, J. W. 2016; 10 (5): 1223-1229

    Abstract

    In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear.To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry.We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other.Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry.Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.

    View details for DOI 10.1016/j.jac1.2016.07.011

    View details for PubMedID 27678440

  • Standards of Evidence and Mechanistic Inference in Autosomal Recessive Hypercholesterolemia ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Priest, J. R., Knowles, J. W. 2016; 36 (8): 1465-1466

    View details for DOI 10.1161/ATVBAHA.116.307714

    View details for Web of Science ID 000381474000002

    View details for PubMedID 27466618

  • Statins in Familial Hypercholesterolemia Translating Evidence to Action JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Knowles, J. W. 2016; 68 (3): 261–64

    View details for PubMedID 27417003

  • Enough Evidence, Time to Act! CIRCULATION Rodriguez, F., Knowles, J. W. 2016; 134 (1): 20-23
  • Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States Data From the CASCADE-FH Registry CIRCULATION-CARDIOVASCULAR GENETICS DeGoma, E. M., Ahmad, Z. S., O'Brien, E. C., Kindt, I., Shrader, P., Newman, C. B., Pokharel, Y., Baum, S. J., Hemphill, L. C., Hudgins, L. C., Ahmed, C. D., Gidding, S. S., Duffy, D., Neal, W., Wilemon, K., Roe, M. T., Rader, D. J., Ballantyne, C. M., Linton, M. F., Duell, P. B., Shapiro, M. D., Moriarty, P. M., Knowles, J. W. 2016; 9 (3): 240-?

    Abstract

    Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap.We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41).FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

    View details for DOI 10.1161/CIRCGENETICS.116.001381

    View details for PubMedID 27013694

  • Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity NATURE MEDICINE Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S., Sharma, A., Holmstrom, A., Chang, A. C., Coronado, M. J., Ebert, A. D., Knowles, J. W., Telli, M. L., Witteles, R. M., Blau, H. M., Bernstein, D., Altman, R. B., Wu, J. C. 2016; 22 (5): 547-556

    Abstract

    Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

    View details for DOI 10.1038/nm.4087

    View details for PubMedID 27089514

  • Impact of Septal Reduction on Left Atrial Size and Diastole in Hypertrophic Cardiomyopathy ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Finocchiaro, G., Haddad, F., Kobayashi, Y., Lee, D., Pavlovic, A., Schnittger, I., Sinagra, G., Magavern, E., Myers, J., Froelicher, V., Knowles, J. W., Ashley, E. 2016; 33 (5): 686-694

    Abstract

    Both myectomy and alcohol septal ablation (ASA) can substantially reduce left ventricular (LV) outflow obstruction, relieve symptoms, and improve outcomes in hypertrophic cardiomyopathy (HCM). It is unclear whether septal reduction decreases left atrial (LA) size and improves diastolic function. The aim of this study was to analyze the consequences of septal reduction on LA size and diastolic function in a cohort of patients with HCM.Forty patients (mean age: 50 ± 14, male sex 64%) with HCM who underwent septal reduction (myectomy or alcohol septal ablation) were studied. Retrospective analyses of echocardiograms preprocedure, postprocedure, and at 1 year of follow-up were performed.Thirty-one patients had septal myectomy and 9 ASA. The degree of reduction in rest peak LV outflow tract gradient was significant (57 ± 32 vs. 23 ± 20 mmHg at 1 year, P < 0.001). Maximal interventricular septal thickness decreased from 22 ± 6 mm preprocedure to 19 ± 4 mm postprocedure (P < 0.001); moderate-to-severe mitral regurgitation (MR) was initially present in 34% of the sample and only 2% after the procedure. Average LA volume index (LAVI) decreased from 63 ± 20 to 55 ± 20 mL/m(2) at the 1-year follow-up (P < 0.001). We did not observe a significant improvement in diastolic function at Doppler (E/A 1.2 ± 0.4 vs. 1.1 ± 0.5, P = 0.07; E' 7.6 ± 3.6 vs. 6.9 ± 3.0, P = 0.4) pre- and postprocedure, respectively). At 1 year, only 5% of the patients were severely symptomatic (NYHA III). On multivariate analysis, a significant change in the LVOT gradient during stress (Δ gradient ≥30 mmHg) was the only variable independently associated with LAVI reverse remodeling >10 mL/m(2) [OR = 6.4 (CI 95% 1.12-36.44), P = 0.04].Septal reduction is effective in the relief of LV obstruction and symptoms in patients with HCM. The hemodynamic changes result in a significant LA reverse remodeling, but not in an improvement of diastolic function in these patients.

    View details for DOI 10.1111/echo.13158

    View details for PubMedID 26926154

  • Usual Blood Pressure and New-Onset Diabetes Risk JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Knowles, J. W., Reaven, G. 2016; 67 (13): 1656–57

    View details for DOI 10.1016/j.jacc.2015.12.065

    View details for Web of Science ID 000372893300019

    View details for PubMedID 27150694

  • Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists. Current atherosclerosis reports Sarraju, A., Kim, S. H., Knowles, J. W. 2016; 18 (2): 7-?

    Abstract

    Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function.

    View details for DOI 10.1007/s11883-016-0558-5

    View details for PubMedID 26782825

  • Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring JAMA PEDIATRICS Priest, J. R., Yang, W., Reaven, G., Knowles, J. W., Shaw, G. M. 2015; 169 (12): 1112-1116

    Abstract

    There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations.To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin.Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79).These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.

    View details for DOI 10.1001/jamapediatrics.2015.2831

    View details for Web of Science ID 000366334600014

    View details for PubMedID 26457543

    View details for PubMedCentralID PMC4996656

  • The Agenda for Familial Hypercholesterolemia A Scientific Statement From the American Heart Association CIRCULATION Gidding, S. S., Champagne, M., de Ferranti, S. D., Defesche, J., Ito, M. K., Knowles, J. W., McCrindle, B., Raal, F., Rader, D., Santos, R. D., Lopes-Virella, M., Watts, G. F., Wierzbicki, A. S., Amer Heart Assoc 2015; 132 (22): 2167–92

    View details for DOI 10.1161/CIR.0000000000000297

    View details for Web of Science ID 000366187100010

    View details for PubMedID 26510694

  • Familial Hypercholesterolemia and the 2013 American College of Cardiology/American Heart Association Guidelines: Myths, Oversimplification, and Misinterpretation Versus Facts AMERICAN JOURNAL OF CARDIOLOGY Knowles, J. W., Stone, N. J., Ballantyne, C. M. 2015; 116 (3): 481-484

    Abstract

    Familial hypercholesterolemia (FH) is a genetic condition resulting in severe, lifelong elevations in low-density lipoprotein cholesterol and a marked increased risk of early-onset coronary disease. FH is treatable when identified, yet is vastly under-recognized and undertreated. Although the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of cholesterol presented a paradigm shift, we believe that there have been serious oversimplifications, misinterpretations, and erroneous reporting about the current ACC/AHA cholesterol guidelines that have contributed to suboptimal care for these subjects. In summary, the ACC/AHA guidelines place tremendous emphasis on the identification of patients with FH, the initiation of high-intensity statin therapy, the need to obtain follow-up lipid values to assess the efficacy and compliance to lifestyle and medical therapy, and the role of nonstatin drugs when needed for optimal care of the individual patient.

    View details for Web of Science ID 000359034100024

    View details for PubMedID 26043952

  • Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes DIABETES Fall, T., Xie, W., Poon, W., Yaghootkar, H., Maegi, R., Knowles, J. W., Lyssenko, V., Weedon, M., Frayling, T. M., Ingelsson, E. 2015; 64 (7): 2676-2684

    Abstract

    The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (β = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C (β = -0.21, P = 5 × 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.

    View details for DOI 10.2337/db14-1710

    View details for Web of Science ID 000356934000049

    View details for PubMedID 25948681

  • Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology Bent, R. E., Wheeler, M. T., Hadley, D., Knowles, J. W., Pavlovic, A., Finocchiaro, G., Haddad, F., Salisbury, H., Race, S., Shmargad, Y., Matheson, G. O., Kumar, N., Saini, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 65 (22): 2462-2463

    View details for DOI 10.1016/j.jacc.2015.03.559

    View details for PubMedID 26046742

  • Prevalence and Prognostic Role of Right Ventricular Involvement in Stress-Induced Cardiomyopathy JOURNAL OF CARDIAC FAILURE Finocchiaro, G., Kobayashi, Y., Magavern, E., Zhou, J. Q., Ashley, E., Sinagra, G., Schnittger, I., Knowles, J. W., Fearon, W. F., Haddad, F., Tremmel, J. A. 2015; 21 (5): 419-425

    Abstract

    Stress-induced cardiomyopathy (SCM) is a reversible cardiomyopathy observed in patients without significant coronary disease. The aim of this study was to assess the incidence and clinical significance of right ventricular (RV) involvement in SCM.We retrospectively analyzed echocardiograms from 40 consecutive patients who presented with SCM at Stanford University Medical Center from September 2000 to November 2010. The primary end point was overall mortality. RV involvement was observed in 20 patients (50%; global RV hypokinesia in 15 patients and focal RV apical akinesia in 5 patients). The independent correlates of RV involvement were older age (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.7two, P = .01) and LVEF (per 10% decrease: OR 3.60, CI 1.77-7.32; P = .02). At a mean follow-up of 44 ± 32 months, 12 patients (30%) died (in-hospital death in 3 patients). At multivariate analysis, the presence of an RV fractional area change <35% emerged as an independent predictor of death (OR 3.6, CI 1.06-12.41; P = .04).RV involvement is a common finding in SCM, and may present as either global or focal RV apical involvement. Both older age and lower LVEF are associated with a higher risk of RV involvement, which appears to be a major predictor of death.

    View details for DOI 10.1016/j.cardfail.2015.02.001

    View details for PubMedID 25704104

  • Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment. JACC. Heart failure Finocchiaro, G., Haddad, F., Knowles, J. W., Caleshu, C., Pavlovic, A., Homburger, J., Shmargad, Y., Sinagra, G., Magavern, E., Wong, M., Perez, M., Schnittger, I., Myers, J., Froelicher, V., Ashley, E. A. 2015; 3 (5): 408-418

    Abstract

    This study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM).The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear.The study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation).Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R(2) of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E' (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R(2) = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m(2) (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036).In HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.

    View details for DOI 10.1016/j.jchf.2014.11.011

    View details for PubMedID 25863972

  • Genetically Determined Height and Coronary Artery Disease NEW ENGLAND JOURNAL OF MEDICINE Nelson, C. P., Hamby, S. E., Saleheen, D., Hopewell, J. C., Zeng, L., Assimes, T. L., Kanoni, S., WILLENBORG, C., Burgess, S., Amouyel, P., Anand, S., Blankenberg, S., Boehm, B. O., Clarke, R. J., Collins, R., Dedoussis, G., Farrall, M., Franks, P. W., Groop, L., Hall, A. S., Hamsten, A., Hengstenberg, C., Hovingh, G. K., Ingelsson, E., Kathiresan, S., Kee, F., Koenig, I. R., Kooner, J., Lehtimaeki, T., Maerz, W., Mcpherson, R., Metspalu, A., NIEMINEN, M. S., O'Donnell, C. J., Palmer, C. N., Peters, A., Perola, M., Reilly, M. P., Ripatti, S., Roberts, R., Salomaa, V., Shah, S. H., Schreiber, S., Siegbahn, A., Thorsteinsdottir, U., Veronesi, G., Wareham, N., Willer, C. J., Zalloua, P. A., Erdmann, J., Deloukas, P., Watkins, H., Schunkert, H., Danesh, J., Thompson, J. R., Samani, N. J. 2015; 372 (17): 1608-1618

    Abstract

    The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).

    View details for DOI 10.1056/NEJMoa1404881

    View details for Web of Science ID 000353294000006

    View details for PubMedID 25853659

  • Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene JOURNAL OF CLINICAL INVESTIGATION Knowles, J. W., Xie, W., Zhang, Z., Chennemsetty, I., Assimes, T. L., Paananen, J., Hansson, O., Pankow, J., Goodarzi, M. O., Carcamo-Orive, I., Morris, A. P., Chen, Y. I., Maekinen, V., Ganna, A., Mahajan, A., Guo, X., Abbasi, F., Greenawalt, D. M., Lum, P., Molony, C., Lind, L., Lindgren, C., Raffel, L. J., Tsao, P. S., Schadt, E. E., Rotter, J. I., Sinaiko, A., Reaven, G., Yang, X., Hsiung, C. A., Groop, L., Cordell, H. J., Laakso, M., Hao, K., Ingelsson, E., Frayling, T. M., Weedon, M. N., Walker, M., Quertermous, T. 2015; 125 (4): 1739-1751

    Abstract

    Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

    View details for DOI 10.1172/JCI74592

    View details for Web of Science ID 000352248600037

    View details for PubMedID 25798622

  • The Independent Predictive Value of Peak Oxygen Consumption, Left ventricular Strain and Atrial Remodelling in Patients With Dilated Cardiomyopathy Boulate, D., Banerjee, D., Ariyama, M., Wheeler, M., Knowles, J. W., Kobayashi, Y., Perez, M., Wu, J., Schnittger, I., Kouznetsova, T., Myers, J., Haddad, F., Ashley, E. A. ELSEVIER SCIENCE INC. 2015: S186
  • PCSK9 Inhibition: Current Concepts and Lessons from Human Genetics CURRENT ATHEROSCLEROSIS REPORTS Rodriguez, F., Knowles, J. W. 2015; 17 (3)

    Abstract

    Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Statins are the cornerstone of therapy for the treatment of elevated LDL-C and for the primary and secondary prevention of ASCVD. However, some patients are intolerant of statins or are unable to achieve acceptable lipid levels on statin-based regimens alone. Proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important regulator of hepatocyte LDL receptor expression and degradation, and recent genetic studies have highlighted the critical role of PCSK9 in human disease. Gain-of-function mutations in PCSK9 are associated with familial hypercholesterolemia, whereas loss-of-function mutations are protective against ASCVD. Therefore, PCSK9 inhibition offers a promising supplement or alternative to statin therapy in the reduction of LDL-C. Numerous phase II and III randomized control trials have demonstrated the tolerability of monoclonal antibodies against PCSK9 and their efficacy in lowering LDL-C by an additional 40-70 %. In this article, we review the growing role of PSCK9 inhibition in LDL-C reduction for diverse patient populations.

    View details for DOI 10.1007/s11883-015-0487-8

    View details for Web of Science ID 000349629400002

    View details for PubMedID 25637042

  • Genetic studies of body mass index yield new insights for obesity biology. Nature Locke, A. E., Kahali, B., Berndt, S. I., Justice, A. E., Pers, T. H., Day, F. R., Powell, C., Vedantam, S., Buchkovich, M. L., Yang, J., Croteau-Chonka, D. C., Esko, T., Fall, T., Ferreira, T., Gustafsson, S., Kutalik, Z., Luan, J., Mägi, R., Randall, J. C., Winkler, T. W., Wood, A. R., Workalemahu, T., Faul, J. D., Smith, J. A., Hua Zhao, J., Zhao, W., Chen, J., Fehrmann, R., Hedman, Å. K., Karjalainen, J., Schmidt, E. M., Absher, D., Amin, N., Anderson, D., Beekman, M., Bolton, J. L., Bragg-Gresham, J. L., Buyske, S., Demirkan, A., Deng, G., Ehret, G. B., Feenstra, B., Feitosa, M. F., Fischer, K., Goel, A., Gong, J., Jackson, A. U., Kanoni, S., Kleber, M. E., Kristiansson, K., Lim, U., Lotay, V., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Medland, S. E., Nalls, M. A., Palmer, C. D., Pasko, D., Pechlivanis, S., Peters, M. J., Prokopenko, I., Shungin, D., Stancáková, A., Strawbridge, R. J., Ju Sung, Y., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S. W., van Setten, J., van Vliet-Ostaptchouk, J. V., Wang, Z., Yengo, L., Zhang, W., Isaacs, A., Albrecht, E., Ärnlöv, J., Arscott, G. M., Attwood, A. P., Bandinelli, S., Barrett, A., Bas, I. N., Bellis, C., Bennett, A. J., Berne, C., Blagieva, R., Blüher, M., Böhringer, S., Bonnycastle, L. L., Böttcher, Y., Boyd, H. A., Bruinenberg, M., Caspersen, I. H., Ida Chen, Y., Clarke, R., Warwick Daw, E., de Craen, A. J., Delgado, G., Dimitriou, M., Doney, A. S., Eklund, N., Estrada, K., Eury, E., Folkersen, L., Fraser, R. M., Garcia, M. E., Geller, F., Giedraitis, V., Gigante, B., Go, A. S., Golay, A., Goodall, A. H., Gordon, S. D., Gorski, M., Grabe, H., Grallert, H., Grammer, T. B., Gräßler, J., Grönberg, H., Groves, C. J., Gusto, G., Haessler, J., Hall, P., Haller, T., Hallmans, G., Hartman, C. A., Hassinen, M., Hayward, C., Heard-Costa, N. L., Helmer, Q., Hengstenberg, C., Holmen, O., Hottenga, J., James, A. L., Jeff, J. M., Johansson, Å., Jolley, J., Juliusdottir, T., Kinnunen, L., Koenig, W., Koskenvuo, M., Kratzer, W., Laitinen, J., Lamina, C., Leander, K., Lee, N. R., Lichtner, P., Lind, L., Lindström, J., Sin Lo, K., Lobbens, S., Lorbeer, R., Lu, Y., Mach, F., Magnusson, P. K., Mahajan, A., McArdle, W. L., McLachlan, S., Menni, C., Merger, S., Mihailov, E., Milani, L., Moayyeri, A., Monda, K. L., Morken, M. A., Mulas, A., Müller, G., Müller-Nurasyid, M., Musk, A. W., Nagaraja, R., Nöthen, M. M., Nolte, I. M., Pilz, S., Rayner, N. W., Renstrom, F., Rettig, R., Ried, J. S., Ripke, S., Robertson, N. R., Rose, L. M., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F. R., Scott, W. R., Seufferlein, T., Shi, J., Vernon Smith, A., Smolonska, J., Stanton, A. V., Steinthorsdottir, V., Stirrups, K., Stringham, H. M., Sundström, J., Swertz, M. A., Swift, A. J., Syvänen, A., Tan, S., Tayo, B. O., Thorand, B., Thorleifsson, G., Tyrer, J. P., Uh, H., Vandenput, L., Verhulst, F. C., Vermeulen, S. H., Verweij, N., Vonk, J. M., Waite, L. L., Warren, H. R., Waterworth, D., Weedon, M. N., Wilkens, L. R., Willenborg, C., Wilsgaard, T., Wojczynski, M. K., Wong, A., Wright, A. F., Zhang, Q., Brennan, E. P., Choi, M., Dastani, Z., Drong, A. W., Eriksson, P., Franco-Cereceda, A., Gådin, J. R., Gharavi, A. G., Goddard, M. E., Handsaker, R. E., Huang, J., Karpe, F., Kathiresan, S., Keildson, S., Kiryluk, K., Kubo, M., Lee, J., Liang, L., Lifton, R. P., Ma, B., McCarroll, S. A., McKnight, A. J., Min, J. L., Moffatt, M. F., Montgomery, G. W., Murabito, J. M., Nicholson, G., Nyholt, D. R., Okada, Y., Perry, J. R., Dorajoo, R., Reinmaa, E., Salem, R. M., Sandholm, N., Scott, R. A., Stolk, L., Takahashi, A., Tanaka, T., van't Hooft, F. M., Vinkhuyzen, A. A., Westra, H., Zheng, W., Zondervan, K. T., Heath, A. C., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Blangero, J., Bovet, P., Campbell, H., Caulfield, M. J., Cesana, G., Chakravarti, A., Chasman, D. I., Chines, P. S., Collins, F. S., Crawford, D. C., Adrienne Cupples, L., Cusi, D., Danesh, J., de Faire, U., Den Ruijter, H. M., Dominiczak, A. F., Erbel, R., Erdmann, J., Eriksson, J. G., Farrall, M., Felix, S. B., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N. G., Forrester, T., Franco, O. H., Gansevoort, R. T., Gejman, P. V., Gieger, C., Gottesman, O., Gudnason, V., Gyllensten, U., Hall, A. S., Harris, T. B., Hattersley, A. T., Hicks, A. A., Hindorff, L. A., Hingorani, A. D., Hofman, A., Homuth, G., Kees Hovingh, G., Humphries, S. E., Hunt, S. C., Hyppönen, E., Illig, T., Jacobs, K. B., Jarvelin, M., Jöckel, K., Johansen, B., Jousilahti, P., Wouter Jukema, J., Jula, A. M., Kaprio, J., Kastelein, J. J., Keinanen-Kiukaanniemi, S. M., Kiemeney, L. A., Knekt, P., Kooner, J. S., Kooperberg, C., Kovacs, P., Kraja, A. T., Kumari, M., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lyssenko, V., Männistö, S., Marette, A., Matise, T. C., McKenzie, C. A., McKnight, B., Moll, F. L., Morris, A. D., Morris, A. P., Murray, J. C., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Madden, P. A., Pasterkamp, G., Peden, J. F., Peters, A., Postma, D. S., Pramstaller, P. P., Price, J. F., Qi, L., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ridker, P. M., Rioux, J. D., Ritchie, M. D., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schunkert, H., Schwarz, P. E., Sever, P., Shuldiner, A. R., Sinisalo, J., Stolk, R. P., Strauch, K., Tönjes, A., Trégouët, D., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M., Völker, U., Waeber, G., Willemsen, G., Witteman, J. C., Zillikens, M. C., Adair, L. S., Amouyel, P., Asselbergs, F. W., Assimes, T. L., Bochud, M., Boehm, B. O., Boerwinkle, E., Bornstein, S. R., Bottinger, E. P., Bouchard, C., Cauchi, S., Chambers, J. C., Chanock, S. J., Cooper, R. S., de Bakker, P. I., Dedoussis, G., Ferrucci, L., Franks, P. W., Froguel, P., Groop, L. C., Haiman, C. A., Hamsten, A., Hui, J., Hunter, D. J., Hveem, K., Kaplan, R. C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N. G., März, W., Melbye, M., Metspalu, A., Moebus, S., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Power, C., Quertermous, T., Rauramaa, R., Rivadeneira, F., Saaristo, T. E., Saleheen, D., Sattar, N., Schadt, E. E., Schlessinger, D., Eline Slagboom, P., Snieder, H., Spector, T. D., Thorsteinsdottir, U., Stumvoll, M., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van der Harst, P., Walker, M., Wallaschofski, H., Wareham, N. J., Watkins, H., Weir, D. R., Wichmann, H., Wilson, J. F., Zanen, P., Borecki, I. B., Deloukas, P., Fox, C. S., Heid, I. M., O'Connell, J. R., Strachan, D. P., Stefansson, K., van Duijn, C. M., Abecasis, G. R., Franke, L., Frayling, T. M., McCarthy, M. I., Visscher, P. M., Scherag, A., Willer, C. J., Boehnke, M., Mohlke, K. L., Lindgren, C. M., Beckmann, J. S., Barroso, I., North, K. E., Ingelsson, E., Hirschhorn, J. N., Loos, R. J., Speliotes, E. K. 2015; 518 (7538): 197-206

    Abstract

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

    View details for DOI 10.1038/nature14177

    View details for PubMedID 25673413

    View details for PubMedCentralID PMC4382211

  • New genetic loci link adipose and insulin biology to body fat distribution. Nature Shungin, D., Winkler, T. W., Croteau-Chonka, D. C., Ferreira, T., Locke, A. E., Mägi, R., Strawbridge, R. J., Pers, T. H., Fischer, K., Justice, A. E., Workalemahu, T., Wu, J. M., Buchkovich, M. L., Heard-Costa, N. L., Roman, T. S., Drong, A. W., Song, C., Gustafsson, S., Day, F. R., Esko, T., Fall, T., Kutalik, Z., Luan, J., Randall, J. C., Scherag, A., Vedantam, S., Wood, A. R., Chen, J., Fehrmann, R., Karjalainen, J., Kahali, B., Liu, C., Schmidt, E. M., Absher, D., Amin, N., Anderson, D., Beekman, M., Bragg-Gresham, J. L., Buyske, S., Demirkan, A., Ehret, G. B., Feitosa, M. F., Goel, A., Jackson, A. U., Johnson, T., Kleber, M. E., Kristiansson, K., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Palmer, C. D., Pasko, D., Pechlivanis, S., Peters, M. J., Prokopenko, I., Stancáková, A., Ju Sung, Y., Tanaka, T., Teumer, A., van Vliet-Ostaptchouk, J. V., Yengo, L., Zhang, W., Albrecht, E., Ärnlöv, J., Arscott, G. M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A. J., Berne, C., Blüher, M., Böhringer, S., Bonnet, F., Böttcher, Y., Bruinenberg, M., Carba, D. B., Caspersen, I. H., Clarke, R., Daw, E. W., Deelen, J., Deelman, E., Delgado, G., Doney, A. S., Eklund, N., Erdos, M. R., Estrada, K., Eury, E., Friedrich, N., Garcia, M. E., Giedraitis, V., Gigante, B., Go, A. S., Golay, A., Grallert, H., Grammer, T. B., Gräßler, J., Grewal, J., Groves, C. J., Haller, T., Hallmans, G., Hartman, C. A., Hassinen, M., Hayward, C., Heikkilä, K., Herzig, K., Helmer, Q., Hillege, H. L., Holmen, O., Hunt, S. C., Isaacs, A., Ittermann, T., James, A. L., Johansson, I., Juliusdottir, T., Kalafati, I., Kinnunen, L., Koenig, W., Kooner, I. K., Kratzer, W., Lamina, C., Leander, K., Lee, N. R., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Mach, F., Magnusson, P. K., Mahajan, A., McArdle, W. L., Menni, C., Merger, S., Mihailov, E., Milani, L., Mills, R., Moayyeri, A., Monda, K. L., Mooijaart, S. P., Mühleisen, T. W., Mulas, A., Müller, G., Müller-Nurasyid, M., Nagaraja, R., Nalls, M. A., Narisu, N., Glorioso, N., Nolte, I. M., Olden, M., Rayner, N. W., Renstrom, F., Ried, J. S., Robertson, N. R., Rose, L. M., Sanna, S., Scharnagl, H., Scholtens, S., Sennblad, B., Seufferlein, T., Sitlani, C. M., Vernon Smith, A., Stirrups, K., Stringham, H. M., Sundström, J., Swertz, M. A., Swift, A. J., Syvänen, A., Tayo, B. O., Thorand, B., Thorleifsson, G., Tomaschitz, A., Troffa, C., van Oort, F. V., Verweij, N., Vonk, J. M., Waite, L. L., Wennauer, R., Wilsgaard, T., Wojczynski, M. K., Wong, A., Zhang, Q., Hua Zhao, J., Brennan, E. P., Choi, M., Eriksson, P., Folkersen, L., Franco-Cereceda, A., Gharavi, A. G., Hedman, Å. K., Hivert, M., Huang, J., Kanoni, S., Karpe, F., Keildson, S., Kiryluk, K., Liang, L., Lifton, R. P., Ma, B., McKnight, A. J., McPherson, R., Metspalu, A., Min, J. L., Moffatt, M. F., Montgomery, G. W., Murabito, J. M., Nicholson, G., Nyholt, D. R., Olsson, C., Perry, J. R., Reinmaa, E., Salem, R. M., Sandholm, N., Schadt, E. E., Scott, R. A., Stolk, L., Vallejo, E. E., Westra, H., Zondervan, K. T., Amouyel, P., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Blangero, J., Brown, M. J., Burnier, M., Campbell, H., Chakravarti, A., Chines, P. S., Claudi-Boehm, S., Collins, F. S., Crawford, D. C., Danesh, J., de Faire, U., de Geus, E. J., Dörr, M., Erbel, R., Eriksson, J. G., Farrall, M., Ferrannini, E., Ferrières, J., Forouhi, N. G., Forrester, T., Franco, O. H., Gansevoort, R. T., Gieger, C., Gudnason, V., Haiman, C. A., Harris, T. B., Hattersley, A. T., Heliövaara, M., Hicks, A. A., Hingorani, A. D., Hoffmann, W., Hofman, A., Homuth, G., Humphries, S. E., Hyppönen, E., Illig, T., Jarvelin, M., Johansen, B., Jousilahti, P., Jula, A. M., Kaprio, J., Kee, F., Keinanen-Kiukaanniemi, S. M., Kooner, J. S., Kooperberg, C., Kovacs, P., Kraja, A. T., Kumari, M., Kuulasmaa, K., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lyssenko, V., Männistö, S., Marette, A., Matise, T. C., McKenzie, C. A., McKnight, B., Musk, A. W., Möhlenkamp, S., Morris, A. D., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Palmer, L. J., Penninx, B. W., Peters, A., Pramstaller, P. P., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ridker, P. M., Ritchie, M. D., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schwarz, P. E., Shuldiner, A. R., Staessen, J. A., Steinthorsdottir, V., Stolk, R. P., Strauch, K., Tönjes, A., Tremblay, A., Tremoli, E., Vohl, M., Völker, U., Vollenweider, P., Wilson, J. F., Witteman, J. C., Adair, L. S., Bochud, M., Boehm, B. O., Bornstein, S. R., Bouchard, C., Cauchi, S., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Cooper, R. S., Dedoussis, G., Ferrucci, L., Froguel, P., Grabe, H., Hamsten, A., Hui, J., Hveem, K., Jöckel, K., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., März, W., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Power, C., Quertermous, T., Rauramaa, R., Rivadeneira, F., Saaristo, T. E., Saleheen, D., Sinisalo, J., Slagboom, P. E., Snieder, H., Spector, T. D., Thorsteinsdottir, U., Stumvoll, M., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van der Harst, P., Veronesi, G., Walker, M., Wareham, N. J., Watkins, H., Wichmann, H., Abecasis, G. R., Assimes, T. L., Berndt, S. I., Boehnke, M., Borecki, I. B., Deloukas, P., Franke, L., Frayling, T. M., Groop, L. C., Hunter, D. J., Kaplan, R. C., O'Connell, J. R., Qi, L., Schlessinger, D., Strachan, D. P., Stefansson, K., van Duijn, C. M., Willer, C. J., Visscher, P. M., Yang, J., Hirschhorn, J. N., Zillikens, M. C., McCarthy, M. I., Speliotes, E. K., North, K. E., Fox, C. S., Barroso, I., Franks, P. W., Ingelsson, E., Heid, I. M., Loos, R. J., Cupples, L. A., Morris, A. P., Lindgren, C. M., Mohlke, K. L. 2015; 518 (7538): 187-196

    Abstract

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

    View details for DOI 10.1038/nature14132

    View details for PubMedID 25673412

    View details for PubMedCentralID PMC4338562

  • Genetic Applications in Coronary Artery Disease CARDIOVASCULAR GENETICS AND GENOMICS IN CLINICAL PRACTICE Pan, S., Kim, J., Mehta, N. N., Knowles, J. W., Shah, S. J., Arnett, D. K. 2015: 253–64
  • Corrigendum: Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2015; 6: 231-?

    Abstract

    [This corrects the article on p. 254 in vol. 5, PMID: 25136350.].

    View details for DOI 10.3389/fgene.2015.00231

    View details for PubMedID 26217377

  • Genetic Evidence for a Normal-Weight "Metabolically Obese" Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes DIABETES Yaghootkar, H., Scott, R. A., White, C. C., Zhang, W., Speliotes, E., Munroe, P. B., Ehret, G. B., Bis, J. C., Fox, C. S., Walker, M., Borecki, I. B., Knowles, J. W., Yerges-Armstrong, L., Ohlsson, C., Perry, J. R., Chambers, J. C., Kooner, J. S., Franceschini, N., Langenberg, C., Hivert, M., Dastani, Z., Richards, J. B., Semple, R. K., Frayling, T. M. 2014; 63 (12): 4369-4377

    Abstract

    The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.

    View details for DOI 10.2337/db14-0318

    View details for Web of Science ID 000345335500045

    View details for PubMedCentralID PMC4392920

  • Reducing the burden of disease and death from familial hypercholesterolemia: A call to action AMERICAN HEART JOURNAL Knowles, J. W., O'Brien, E. C., Greendale, K., Wilemon, K., Genest, J., Sperling, L. S., Neal, W. A., Rader, D. J., Khoury, M. J. 2014; 168 (6): 807–11

    Abstract

    Familial hypercholesterolemia (FH) is a genetic disease characterized by substantial elevations of low-density lipoprotein cholesterol, unrelated to diet or lifestyle. Untreated FH patients have 20 times the risk of developing coronary artery disease, compared with the general population. Estimates indicate that as many as 1 in 500 people of all ethnicities and 1 in 250 people of Northern European descent may have FH; nevertheless, the condition remains largely undiagnosed. In the United States alone, perhaps as little as 1% of FH patients have been diagnosed. Consequently, there are potentially millions of children and adults worldwide who are unaware that they have a life-threatening condition. In countries like the Netherlands, the United Kingdom, and Spain, cascade screening programs have led to dramatic improvements in FH case identification. Given that there are currently no systematic approaches in the United States to identify FH patients or affected relatives, the patient-centric nonprofit FH Foundation convened a national FH Summit in 2013, where participants issued a "call to action" to health care providers, professional organizations, public health programs, patient advocacy groups, and FH experts, in order to bring greater attention to this potentially deadly, but (with proper diagnosis) eminently treatable, condition.

    View details for PubMedID 25458642

    View details for PubMedCentralID PMC4683103

  • RV remodeling in college athletes engaged in mixed strength and endurance training: do the current echocardiographic reference values apply? Finocchiaro, G., Knowles, J. W., Perez, M., Schnittger, I., Magavern, E., Puryear, J., Sinagra, G., Froelicher, V., Ashley, E., Haddad, F. OXFORD UNIV PRESS. 2014: 729–30
  • Impact of latent obstruction on exercise tolerance in hypertrophic cardiomyopathy Finocchiaro, G., Haddad, F., Knowles, J. W., Pavlovic, A., Sinagra, G., Magavern, E., Wong, M., Myers, J., Froelicher, V., Ashley, E. A. OXFORD UNIV PRESS. 2014: 927
  • Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example FRONTIERS IN GENETICS Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5

    Abstract

    Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

    View details for DOI 10.3389/fgene.2014.00254

    View details for Web of Science ID 000347445200001

  • Hyperuricaemia: the unintended consequence of insulin resistance/compensatory hyperinsulinaemia. Philanthropy gone awry. Journal of internal medicine Knowles, J. W., Reaven, G. 2014; 276 (2): 196-198

    View details for DOI 10.1111/joim.12209

    View details for PubMedID 24471887

  • Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes Dimas, A. S., Lagou, V., Barker, A., Knowles, J. W., Mägi, R., Hivert, M., Benazzo, A., Rybin, D., Jackson, A. U., Stringham, H. M., Song, C., Fischer-Rosinsky, A., Boesgaard, T. W., Grarup, N., Abbasi, F. A., Assimes, T. L., Hao, K., Yang, X., Lecoeur, C., Barroso, I., Bonnycastle, L. L., Böttcher, Y., Bumpstead, S., Chines, P. S., Erdos, M. R., Graessler, J., Kovacs, P., Morken, M. A., Narisu, N., Payne, F., Stancakova, A., Swift, A. J., Tönjes, A., Bornstein, S. R., Cauchi, S., Froguel, P., Meyre, D., Schwarz, P. E., Häring, H., Smith, U., Boehnke, M., Bergman, R. N., Collins, F. S., Mohlke, K. L., Tuomilehto, J., Quertemous, T., Lind, L., Hansen, T., Pedersen, O., Walker, M., Pfeiffer, A. F., Spranger, J., Stumvoll, M., Meigs, J. B., Wareham, N. J., Kuusisto, J., Laakso, M., Langenberg, C., Dupuis, J., Watanabe, R. M., Florez, J. C., Ingelsson, E., McCarthy, M. I., Prokopenko, I. 2014; 63 (6): 2158-2171

    Abstract

    Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

    View details for DOI 10.2337/db13-0949

    View details for PubMedID 24296717

  • Re: "Temporal relationship between uric acid concentration and risk of diabetes in a community-based study population". American journal of epidemiology Knowles, J. W., Reaven, G. 2014; 179 (9): 1147-1148

    View details for DOI 10.1093/aje/kwu055

    View details for PubMedID 24670373

  • Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy. Journal of cardiac failure Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Schnittger, I., Knowles, J. W., Perez, M., Magavern, E., Myers, J., Ashley, E. 2014; 20 (4): 236-243

    Abstract

    Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 ± 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032).Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients.

    View details for DOI 10.1016/j.cardfail.2014.01.014

    View details for PubMedID 24486928

  • Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

    Abstract

    In this article, we describe a double-chambered left ventricle (LV) associated with a functional right ventricular (RV) aneurysm and right atrial (RA) enlargement in an asymptomatic 24-year-old woman with a family history of sudden cardiac death. We will discuss the differential diagnosis, genetic testing and possible prognostic implications.

    View details for DOI 10.1111/echo.12467

    View details for PubMedID 24299065

  • Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. American heart journal O'Brien, E. C., Roe, M. T., Fraulo, E. S., Peterson, E. D., Ballantyne, C. M., Genest, J., Gidding, S. S., Hammond, E., Hemphill, L. C., Hudgins, L. C., Kindt, I., Moriarty, P. M., Ross, J., Underberg, J. A., Watson, K., Pickhardt, D., Rader, D. J., Wilemon, K., Knowles, J. W. 2014; 167 (3): 342-349 e17

    Abstract

    Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members.The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

    View details for DOI 10.1016/j.ahj.2013.12.008

    View details for PubMedID 24576518

  • Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. American heart journal O'Brien, E. C., Roe, M. T., Fraulo, E. S., Peterson, E. D., Ballantyne, C. M., Genest, J., Gidding, S. S., Hammond, E., Hemphill, L. C., Hudgins, L. C., Kindt, I., Moriarty, P. M., Ross, J., Underberg, J. A., Watson, K., Pickhardt, D., Rader, D. J., Wilemon, K., Knowles, J. W. 2014; 167 (3): 342-349 e17

    Abstract

    Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members.The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

    View details for DOI 10.1016/j.ahj.2013.12.008

    View details for PubMedID 24576518

  • Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

    View details for DOI 10.1111/echo.12467

    View details for PubMedID 24299065

  • Prevalence and clinical correlates of right ventricular dysfunction in patients with hypertrophic cardiomyopathy. American journal of cardiology Finocchiaro, G., Knowles, J. W., Pavlovic, A., Perez, M., Magavern, E., Sinagra, G., Haddad, F., Ashley, E. A. 2014; 113 (2): 361-367

    Abstract

    Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.

    View details for DOI 10.1016/j.amjcard.2013.09.045

    View details for PubMedID 24230980

  • How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

    Abstract

    It is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.Tertiary referral centre from Stanford, California, USA.383 patients with HCM and normal systolic function between 1999 and 2011. A group of 100 prospectively recruited age-matched and sex-matched healthy participants were used as controls.Echocardiograms were assessed by two blinded board-certified cardiologists. HCM morphology was classified as described in the literature (reverse, sigmoid, symmetric, apical and undefined).Reverse curvature morphology was most commonly observed (218 (57%). Lateral mitral annular E'<12 cm/s was present in 86% of reverse, 88% of sigmoid, 79% of symmetric, 86% of apical and 81% of undefined morphology, p=0.65. E/E' was similarly elevated (E/E': 12.3±7.9 in reverse curvature, 12.1±6.1 in sigmoid, 12.7±9.5 in symmetric, 9.4±4.0 in apical, 12.7±7.9 in undefined morphology, p=0.71) and indexed left atrial volume (LAVi)>40 mL/m(2) was present in 47% in reverse curvature, 33% in sigmoid, 32% in symmetric, 37% in apical and 32% in undefined, p=0.09. Each morphology showed altered parameters of diastolic function when compared with the control population. Left ventricular (LV) obstruction was independently associated with all three diastolic parameters considered, in particular with LAVi>40 mL/m(2) (OR 2.04 (95% CI 1.23 to 3.39), p=0.005), E/E'>15 (OR 4.66 (95% CI 2.51 to 8.64), p<0.001) and E'<8 (OR 2.55 (95% CI 1.42 to 4.53), p=0.001). Other correlates of diastolic dysfunction were age, LV wall thickness and moderate-to-severe mitral regurgitation.In HCM, diastolic dysfunction is present to similar degrees independently from the morphological pattern. The main correlates of diastolic dysfunction are LV obstruction, age, degree of hypertrophy and degree of mitral regurgitation.

    View details for DOI 10.1136/bmjopen-2014-004814

    View details for PubMedID 24928584

    View details for PubMedCentralID PMC4067898

  • Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes Yaghootkar, H., Scott, R. A., White, C. C., Zhang, W., Speliotes, E., Munroe, P. B., Ehret, G. B., Bis, J. C., Fox, C. S., Walker, M., Borecki, I. B., Knowles, J. W., Yerges-Armstrong, L., Ohlsson, C., Perry, J. R., Chambers, J. C., Kooner, J. S., Franceschini, N., Langenberg, C., Hivert, M. F., Dastani, Z., Richards, J. B., Semple, R. K., Frayling, T. M. 2014; 63 (12): 4369–77

    Abstract

    The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.

    View details for PubMedID 25048195

  • How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

    View details for DOI 10.1136/bmjopen-2014-004814

    View details for PubMedID 24928584

  • Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5: 254-?

    Abstract

    Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

    View details for DOI 10.3389/fgene.2014.00254

    View details for PubMedID 25136350

  • Trans-ethnic fine mapping identifies a novel independent locus at the 3 ' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population DIABETOLOGIA Kuo, J. Z., Sheu, W. H., Assimes, T. L., Hung, Y., Absher, D., Chiu, Y., Mak, J., Wang, J., Kwon, S., Hsu, C., Goodarzi, M. O., Lee, I., Knowles, J. W., Miller, B. E., Lee, W., Juang, J. J., Wang, T., Guo, X., Taylor, K. D., Chuang, L., Hsiung, C. A., Quertermous, T., Rotter, J. I., Chen, Y. I. 2013; 56 (12): 2619-2628

    Abstract

    Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression.We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1.These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.

    View details for DOI 10.1007/s00125-013-3047-1

    View details for Web of Science ID 000326599300010

    View details for PubMedID 24013783

    View details for PubMedCentralID PMC3825282

  • Variation in Use of Left Ventriculography in the Veterans Affairs Health Care System CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Heidenreich, P. A., Lin, S., Knowles, J. W., Perez, M., Maddox, T. M., Ho, M. P., Rumsfeld, J. S., Sahay, A., Massie, B. M., Tsai, T. T., Witteles, R. M. 2013; 6 (6): 687-693

    Abstract

    Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System.We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VA's Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases.There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000199

    View details for Web of Science ID 000330362400017

    View details for PubMedID 24192569

  • Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes. Diabetes Yaghootkar, H., Lamina, C., Scott, R. A., Dastani, Z., Hivert, M., Warren, L. L., Stancáková, A., Buxbaum, S. G., Lyytikäinen, L., Henneman, P., Wu, Y., Cheung, C. Y., Pankow, J. S., Jackson, A. U., Gustafsson, S., Zhao, J. H., Ballantyne, C. M., Xie, W., Bergman, R. N., Boehnke, M., El Bouazzaoui, F., Collins, F. S., Dunn, S. H., Dupuis, J., Forouhi, N. G., Gillson, C., Hattersley, A. T., Hong, J., Kähönen, M., Kuusisto, J., Kedenko, L., Kronenberg, F., Doria, A., Assimes, T. L., Ferrannini, E., Hansen, T., Hao, K., Häring, H., Knowles, J. W., Lindgren, C. M., Nolan, J. J., Paananen, J., Pedersen, O., Quertermous, T., Smith, U., Lehtimäki, T., Liu, C., Loos, R. J., McCarthy, M. I., Morris, A. D., Vasan, R. S., Spector, T. D., Teslovich, T. M., Tuomilehto, J., Van Dijk, K. W., Viikari, J. S., Zhu, N., Langenberg, C., Ingelsson, E., Semple, R. K., Sinaiko, A. R., Palmer, C. N., Walker, M., Lam, K. S., Paulweber, B., Mohlke, K. L., Van Duijn, C., Raitakari, O. T., Bidulescu, A., Wareham, N. J., Laakso, M., Waterworth, D. M., Lawlor, D. A., Meigs, J. B., Richards, J. B., Frayling, T. M. 2013; 62 (10): 3589-3598

    Abstract

    Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

    View details for DOI 10.2337/db13-0128

    View details for PubMedID 23835345

    View details for PubMedCentralID PMC3781444

  • Exercise capacity in patients with hypertrophic cardiomyopathy: non-invasive hemodynamic responses to exercise and association with clinical and imaging variables Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Wong, M., Knowles, J. K., Perez, M., Myers, J., Ashley, E. OXFORD UNIV PRESS. 2013: 532–33
  • Prognostic role of exercise echocardiography in patients with hypertrophic cardiomyopathy Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Magavern, E., Knowles, J. K., Ashley, E. OXFORD UNIV PRESS. 2013: 167
  • The shared allelic architecture of adiponectin levels and coronary artery disease ATHEROSCLEROSIS Dastani, Z., Johnson, T., Kronenberg, F., Nelson, C. P., Assimes, T. L., Maerz, W., Richards, J. B. 2013; 229 (1): 145-148

    Abstract

    OBJECTIVE: A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS: Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS: In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 × 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 × 10(-7)). CONCLUSION: These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.

    View details for DOI 10.1016/j.atherosclerosis.2013.03.034

    View details for Web of Science ID 000320594700023

  • Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations. American journal of human genetics Coram, M. A., Duan, Q., Hoffmann, T. J., Thornton, T., Knowles, J. W., Johnson, N. A., Ochs-Balcom, H. M., Donlon, T. A., Martin, L. W., Eaton, C. B., Robinson, J. G., Risch, N. J., Zhu, X., Kooperberg, C., Li, Y., Reiner, A. P., Tang, H. 2013; 92 (6): 904-916

    Abstract

    Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.

    View details for DOI 10.1016/j.ajhg.2013.04.025

    View details for PubMedID 23726366

    View details for PubMedCentralID PMC3675231

  • Genome-wide Characterization of Shared and Distinct Genetic Components that Influence Blood Lipid Levels in Ethnically Diverse Human Populations AMERICAN JOURNAL OF HUMAN GENETICS Coram, M. A., Duan, Q., Hoffmann, T. J., Thornton, T., Knowles, J. W., Johnson, N. A., Ochs-Balcom, H. M., Donlon, T. A., Martin, L. W., Eaton, C. B., Robinson, J. G., Risch, N. J., Zhu, X., Kooperberg, C., Li, Y., Reiner, A. P., Tang, H. 2013; 92 (6): 904-916

    Abstract

    Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.

    View details for DOI 10.1016/j.ajhg.2013.04.025

    View details for Web of Science ID 000320415300007

    View details for PubMedCentralID PMC3675231

  • Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature genetics Den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., Bochud, M., Boucher, G., Cornelis, M. C., Gudbjartsson, D., Hadley, D., van der Harst, P., Hayward, C., den Heijer, M., Igl, W., Jackson, A. U., Kutalik, Z., Luan, J., Kemp, J. P., Kristiansson, K., Ladenvall, C., Lorentzon, M., Montasser, M. E., Njajou, O. T., O'Reilly, P. F., Padmanabhan, S., St Pourcain, B., Rankinen, T., Salo, P., Tanaka, T., Timpson, N. J., Vitart, V., Waite, L., Wheeler, W., Zhang, W., Draisma, H. H., Feitosa, M. F., Kerr, K. F., Lind, P. A., Mihailov, E., Onland-Moret, N. C., Song, C., Weedon, M. N., Xie, W., Yengo, L., Absher, D., Albert, C. M., Alonso, A., Arking, D. E., de Bakker, P. I., Balkau, B., Barlassina, C., Benaglio, P., Bis, J. C., Bouatia-Naji, N., Brage, S., Chanock, S. J., Chines, P. S., Chung, M., Darbar, D., Dina, C., Dörr, M., Elliott, P., Felix, S. B., Fischer, K., Fuchsberger, C., de Geus, E. J., Goyette, P., Gudnason, V., Harris, T. B., Hartikainen, A., Havulinna, A. S., Heckbert, S. R., Hicks, A. A., Hofman, A., Holewijn, S., Hoogstra-Berends, F., Hottenga, J., Jensen, M. K., Johansson, A., Junttila, J., Kääb, S., Kanon, B., Ketkar, S., Khaw, K., Knowles, J. W., Kooner, A. S., Kors, J. A., Kumari, M., Milani, L., Laiho, P., Lakatta, E. G., Langenberg, C., Leusink, M., Liu, Y., Luben, R. N., Lunetta, K. L., Lynch, S. N., Markus, M. R., Marques-Vidal, P., Mateo Leach, I., McArdle, W. L., McCarroll, S. A., Medland, S. E., Miller, K. A., Montgomery, G. W., Morrison, A. C., Müller-Nurasyid, M., Navarro, P., Nelis, M., O'Connell, J. R., O'Donnell, C. J., Ong, K. K., Newman, A. B., Peters, A., Polasek, O., Pouta, A., Pramstaller, P. P., Psaty, B. M., Rao, D. C., Ring, S. M., Rossin, E. J., Rudan, D., Sanna, S., Scott, R. A., Sehmi, J. S., Sharp, S., Shin, J. T., Singleton, A. B., Smith, A. V., Soranzo, N., Spector, T. D., Stewart, C., Stringham, H. M., Tarasov, K. V., Uitterlinden, A. G., Vandenput, L., Hwang, S., Whitfield, J. B., Wijmenga, C., Wild, S. H., Willemsen, G., Wilson, J. F., Witteman, J. C., Wong, A., Wong, Q., Jamshidi, Y., Zitting, P., Boer, J. M., Boomsma, D. I., Borecki, I. B., van Duijn, C. M., Ekelund, U., Forouhi, N. G., Froguel, P., Hingorani, A., Ingelsson, E., Kivimaki, M., Kronmal, R. A., Kuh, D., Lind, L., Martin, N. G., Oostra, B. A., Pedersen, N. L., Quertermous, T., Rotter, J. I., van der Schouw, Y. T., Verschuren, W. M., Walker, M., Albanes, D., Arnar, D. O., Assimes, T. L., Bandinelli, S., Boehnke, M., de Boer, R. A., Bouchard, C., Caulfield, W. L., Chambers, J. C., Curhan, G., Cusi, D., Eriksson, J., Ferrucci, L., van Gilst, W. H., Glorioso, N., de Graaf, J., Groop, L., Gyllensten, U., Hsueh, W., Hu, F. B., Huikuri, H. V., Hunter, D. J., Iribarren, C., Isomaa, B., Jarvelin, M., Jula, A., Kähönen, M., Kiemeney, L. A., van der Klauw, M. M., Kooner, J. S., Kraft, P., Iacoviello, L., Lehtimäki, T., Lokki, M. L., Mitchell, B. D., Navis, G., Nieminen, M. S., Ohlsson, C., Poulter, N. R., Qi, L., Raitakari, O. T., Rimm, E. B., Rioux, J. D., Rizzi, F., Rudan, I., Salomaa, V., Sever, P. S., Shields, D. C., Shuldiner, A. R., Sinisalo, J., Stanton, A. V., Stolk, R. P., Strachan, D. P., Tardif, J., Thorsteinsdottir, U., Tuomilehto, J., van Veldhuisen, D. J., Virtamo, J., Viikari, J., Vollenweider, P., Waeber, G., Widen, E., Cho, Y. S., Olsen, J. V., Visscher, P. M., Willer, C., Franke, L., Erdmann, J., Thompson, J. R., Pfeufer, A., Sotoodehnia, N., Newton-Cheh, C., Ellinor, P. T., Stricker, B. H., Metspalu, A., Perola, M., Beckmann, J. S., Smith, G. D., Stefansson, K., Wareham, N. J., Munroe, P. B., Sibon, O. C., Milan, D. J., Snieder, H., Samani, N. J., Loos, R. J. 2013; 45 (6): 621-631

    Abstract

    Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

    View details for DOI 10.1038/ng.2610

    View details for PubMedID 23583979

  • Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes. Diabetes Xie, W., Wood, A. R., Lyssenko, V., Weedon, M. N., Knowles, J. W., Alkayyali, S., Assimes, T. L., Quertermous, T., Abbasi, F., Paananen, J., Häring, H., Hansen, T., Pedersen, O., Smith, U., Laakso, M., Dekker, J. M., Nolan, J. J., Groop, L., Ferrannini, E., Adam, K., Gall, W. E., Frayling, T. M., Walker, M. 2013; 62 (6): 2141-2150

    Abstract

    Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.

    View details for DOI 10.2337/db12-0876

    View details for PubMedID 23378610

    View details for PubMedCentralID PMC3661655

  • Genetic Predisposition to Higher Blood Pressure Increases Coronary Artery Disease Risk HYPERTENSION Lieb, W., Jansen, H., Loley, C., Pencina, M. J., Nelson, C. P., Newton-Cheh, C., Kathiresan, S., Reilly, M. P., Assimes, T. L., Boerwinkle, E., Hall, A. S., Hengstenberg, C., Laaksonen, R., McPherson, R., Thorsteinsdottir, U., Ziegler, A., Peters, A., Thompson, J. R., Koenig, I. R., Erdmann, J., Samani, N. J., Vasan, R. S., Schunkert, H. 2013; 61 (5): 995-?

    Abstract

    Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5 × 10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.

    View details for DOI 10.1161/HYPERTENSIONAHA.111.00275

    View details for Web of Science ID 000317718200025

  • Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation Liang, P., Lan, F., Lee, A. S., Gong, T., Sanchez-Freire, V., Wang, Y., Diecke, S., Sallam, K., Knowles, J. W., Wang, P. J., Nguyen, P. K., Bers, D. M., Robbins, R. C., Wu, J. C. 2013; 127 (16): 1677-1691

    Abstract

    Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.

    View details for DOI 10.1161/CIRCULATIONAHA.113.001883

    View details for PubMedID 23519760

    View details for PubMedCentralID PMC3870148

  • Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation Liang, P., Lan, F., Lee, A. S., Gong, T., Sanchez-Freire, V., Wang, Y., Diecke, S., Sallam, K., Knowles, J. W., Wang, P. J., Nguyen, P. K., Bers, D. M., Robbins, R. C., Wu, J. C. 2013; 127 (16): 1677-1691

    View details for DOI 10.1161/CIRCULATIONAHA.113.001883

    View details for PubMedID 23519760

  • Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature genetics Den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., Bochud, M., Boucher, G., Cornelis, M. C., Gudbjartsson, D., Hadley, D., van der Harst, P., Hayward, C., den Heijer, M., Igl, W., Jackson, A. U., Kutalik, Z., Luan, J., Kemp, J. P., Kristiansson, K., Ladenvall, C., Lorentzon, M., Montasser, M. E., Njajou, O. T., O'Reilly, P. F., Padmanabhan, S., St Pourcain, B., Rankinen, T., Salo, P., Tanaka, T., Timpson, N. J., Vitart, V., Waite, L., Wheeler, W., Zhang, W., Draisma, H. H., Feitosa, M. F., Kerr, K. F., Lind, P. A., Mihailov, E., Onland-Moret, N. C., Song, C., Weedon, M. N., Xie, W., Yengo, L., Absher, D., Albert, C. M., Alonso, A., Arking, D. E., de Bakker, P. I., Balkau, B., Barlassina, C., Benaglio, P., Bis, J. C., Bouatia-Naji, N., Brage, S., Chanock, S. J., Chines, P. S., Chung, M., Darbar, D., Dina, C., Dörr, M., Elliott, P., Felix, S. B., Fischer, K., Fuchsberger, C., de Geus, E. J., Goyette, P., Gudnason, V., Harris, T. B., Hartikainen, A., Havulinna, A. S., Heckbert, S. R., Hicks, A. A., Hofman, A., Holewijn, S., Hoogstra-Berends, F., Hottenga, J., Jensen, M. K., Johansson, A., Junttila, J., Kääb, S., Kanon, B., Ketkar, S., Khaw, K., Knowles, J. W., Kooner, A. S., Kors, J. A., Kumari, M., Milani, L., Laiho, P., Lakatta, E. G., Langenberg, C., Leusink, M., Liu, Y., Luben, R. N., Lunetta, K. L., Lynch, S. N., Markus, M. R., Marques-Vidal, P., Mateo Leach, I., McArdle, W. L., McCarroll, S. A., Medland, S. E., Miller, K. A., Montgomery, G. W., Morrison, A. C., Müller-Nurasyid, M., Navarro, P., Nelis, M., O'Connell, J. R., O'Donnell, C. J., Ong, K. K., Newman, A. B., Peters, A., Polasek, O., Pouta, A., Pramstaller, P. P., Psaty, B. M., Rao, D. C., Ring, S. M., Rossin, E. J., Rudan, D., Sanna, S., Scott, R. A., Sehmi, J. S., Sharp, S., Shin, J. T., Singleton, A. B., Smith, A. V., Soranzo, N., Spector, T. D., Stewart, C., Stringham, H. M., Tarasov, K. V., Uitterlinden, A. G., Vandenput, L., Hwang, S., Whitfield, J. B., Wijmenga, C., Wild, S. H., Willemsen, G., Wilson, J. F., Witteman, J. C., Wong, A., Wong, Q., Jamshidi, Y., Zitting, P., Boer, J. M., Boomsma, D. I., Borecki, I. B., van Duijn, C. M., Ekelund, U., Forouhi, N. G., Froguel, P., Hingorani, A., Ingelsson, E., Kivimaki, M., Kronmal, R. A., Kuh, D., Lind, L., Martin, N. G., Oostra, B. A., Pedersen, N. L., Quertermous, T., Rotter, J. I., van der Schouw, Y. T., Verschuren, W. M., Walker, M., Albanes, D., Arnar, D. O., Assimes, T. L., Bandinelli, S., Boehnke, M., de Boer, R. A., Bouchard, C., Caulfield, W. L., Chambers, J. C., Curhan, G., Cusi, D., Eriksson, J., Ferrucci, L., van Gilst, W. H., Glorioso, N., de Graaf, J., Groop, L., Gyllensten, U., Hsueh, W., Hu, F. B., Huikuri, H. V., Hunter, D. J., Iribarren, C., Isomaa, B., Jarvelin, M., Jula, A., Kähönen, M., Kiemeney, L. A., van der Klauw, M. M., Kooner, J. S., Kraft, P., Iacoviello, L., Lehtimäki, T., Lokki, M. L., Mitchell, B. D., Navis, G., Nieminen, M. S., Ohlsson, C., Poulter, N. R., Qi, L., Raitakari, O. T., Rimm, E. B., Rioux, J. D., Rizzi, F., Rudan, I., Salomaa, V., Sever, P. S., Shields, D. C., Shuldiner, A. R., Sinisalo, J., Stanton, A. V., Stolk, R. P., Strachan, D. P., Tardif, J., Thorsteinsdottir, U., Tuomilehto, J., van Veldhuisen, D. J., Virtamo, J., Viikari, J., Vollenweider, P., Waeber, G., Widen, E., Cho, Y. S., Olsen, J. V., Visscher, P. M., Willer, C., Franke, L., Erdmann, J., Thompson, J. R., Pfeufer, A., Sotoodehnia, N., Newton-Cheh, C., Ellinor, P. T., Stricker, B. H., Metspalu, A., Perola, M., Beckmann, J. S., Smith, G. D., Stefansson, K., Wareham, N. J., Munroe, P. B., Sibon, O. C., Milan, D. J., Snieder, H., Samani, N. J., Loos, R. J. 2013; 45 (6): 621-631

    Abstract

    Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

    View details for DOI 10.1038/ng.2610

    View details for PubMedID 23583979

  • Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp. Metabolism Knowles, J. W., Assimes, T. L., Tsao, P. S., Natali, A., Mari, A., Quertermous, T., Reaven, G. M., Abbasi, F. 2013; 62 (4): 548-553

    Abstract

    Two direct measurements of peripheral insulin sensitivity are the M value derived from the euglycemic, hyperinsulinemic clamp (EC) and the steady-state plasma glucose (SSPG) concentration derived from the insulin suppression test (IST). Prior work suggests that these measures are highly correlated, but the agreement between them is unknown. To determine the agreement between SSPG and M and to develop transformation equations to convert SSPG to M and vice versa, we directly compared these two measurements in the same individuals.A total of 15 nondiabetic subjects (9 women and 6 men) underwent both an EC and a modified version of the IST within a median interval of 5days. We performed standard correlation metrics of the two measures and developed transformation regression equations for the two measures.The mean±SD age of the subjects was 57±7years and body mass index, 27.7±3.9kg/m(2). The median (interquartile range) SSPG concentration was 6.7 (5.1, 9.8) mmol/L and M value, 49.6 (28.9, 64.2) μmol/min/kg-LBM. There was a highly significant correlation between SSPG and M (r=-0.87, P <0.001). The relationship was best fit by regression models with exponential/logarithmic functions (R(2)=0.85). Bland-Altman plots demonstrated an excellent agreement between these measures of insulin action.The SSPG and M are highly related measures of insulin sensitivity and the results provide the means to directly compare the two measurements.

    View details for DOI 10.1016/j.metabol.2012.10.002

    View details for PubMedID 23151437

  • Role of international registries in enhancing the care of familial hypercholesterolaemia. International journal of evidence-based healthcare Hammond, E., Watts, G. F., Rubinstein, Y., Farid, W., Livingston, M., Knowles, J. W., Lochmüller, H., Bellgard, M., Dawkins, H. J. 2013; 11 (2): 134–39

    Abstract

    Familial hypercholesterolaemia (FH) is a relatively common genetic disorder associated with high risk of coronary heart disease that is preventable by early diagnosis and treatment. In a previous article, we reviewed the evidence for clinical management, models of care and health economic evaluations. The present commentary emphasises that collective action is needed to strengthen our approaches to evidence-based care, including better diagnosis and access to effective therapies. We detail how contemporary innovations in inter-operable, web-based, open-source and secure registries can provide the supporting infrastructure to: (i) address a current gap in the flow of data for measuring the quality of healthcare; (ii) support basic research through provision of high-quality, de-identified aggregate data; (iii) enable equitable access to clinical trials; and (iv) support efforts to disseminate evidence for best practice and information for care services. We describe how these aspects of enabling infrastructure will be incorporated into the development of a National FH Registry for Australasia, and proffer that a coordinated response to FH would be enhanced through a global network of inter-operable registries.

    View details for DOI 10.1111/1744-1609.12023

    View details for PubMedID 23750577

  • Large-scale association analysis identifies new risk loci for coronary artery disease NATURE GENETICS Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, B. A., Stirrups, K., Koenig, I. R., Cazier, J., Johansson, A., Hall, A. S., Lee, J., Willer, C. J., Chambers, J. C., Esko, T., Folkersen, L., Goel, A., Grundberg, E., Havulinna, A. S., Ho, W. K., Hopewell, J. C., Eriksson, N., Kleber, M. E., Kristiansson, K., Lundmark, P., Lyytikainen, L., Rafelt, S., Shungin, D., Strawbridge, R. J., Thorleifsson, G., Tikkanen, E., Van Zuydam, N., Voight, B. F., Waite, L. L., Zhang, W., Ziegler, A., Absher, D., Altshuler, D., Balmforth, A. J., Barroso, I., Braund, P. S., Burgdorf, C., Claudi-Boehm, S., Cox, D., Dimitriou, M., Do, R., Doney, A. S., El Mokhtari, N., Eriksson, P., Fischer, K., Fontanillas, P., Franco-Cereceda, A., Gigante, B., Groop, L., Gustafsson, S., Hager, J., Hallmans, G., Han, B., Hunt, S. E., Kang, H. M., Illig, T., Kessler, T., Knowles, J. W., Kolovou, G., Kuusisto, J., Langenberg, C., Langford, C., Leander, K., Lokki, M., Lundmark, A., McCarthy, M. I., Meisinger, C., Melander, O., Mihailov, E., Maouche, S., Morris, A. D., Mueller-Nurasyid, M., Nikus, K., Peden, J. F., Rayner, N. W., Rasheed, A., Rosinger, S., Rubin, D., Rumpf, M. P., Schaefer, A., Sivananthan, M., Song, C., Stewart, A. F., Tan, S., Thorgeirsson, G., van der Schoot, C. E., Wagner, P. J., Wells, G. A., Wild, P. S., Yang, T., Amouyel, P., Arveiler, D., Basart, H., Boehnke, M., Boerwinkle, E., Brambilla, P., Cambien, F., Cupples, A. L., de Faire, U., Dehghan, A., Diemert, P., Epstein, S. E., Evans, A., Ferrario, M. M., Ferrieres, J., Gauguier, D., Go, A. S., Goodall, A. H., Gudnason, V., Hazen, S. L., Holm, H., Iribarren, C., Jang, Y., Kahonen, M., Kee, F., Kim, H., Klopp, N., Koenig, W., Kratzer, W., Kuulasmaa, K., Laakso, M., Laaksonen, R., Lee, J., Lind, L., Ouwehand, W. H., Parish, S., Park, J. E., Pedersen, N. L., Peters, A., Quertermous, T., Rader, D. J., Salomaa, V., Schadt, E., Shah, S. H., Sinisalo, J., Stark, K., Stefansson, K., Tregouet, D., Virtamo, J., Wallentin, L., Wareham, N., Zimmermann, M. E., Nieminen, M. S., Hengstenberg, C., Sandhu, M. S., Pastinen, T., Syvanen, A., Hovingh, G. K., Dedoussis, G., Franks, P. W., Lehtimaki, T., Metspalu, A., Zalloua, P. A., Siegbahn, A., Schreiber, S., Ripatti, S., Blankenberg, S. S., Perola, M., Clarke, R., Boehm, B. O., O'Donnell, C., Reilly, M. P., Maerz, W., Collins, R., Kathiresan, S., Hamsten, A., Kooner, J. S., Thorsteinsdottir, U., Danesh, J., Palmer, C. N., Roberts, R., Watkins, H., Schunkert, H., Samani, N. J. 2013; 45 (1): 25-U52

    Abstract

    Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

    View details for DOI 10.1038/ng.2480

    View details for Web of Science ID 000312838800009

    View details for PubMedID 23202125

  • Large-scale association analysis identifies new risk loci for coronary artery disease. Nature genetics Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, B. A., Stirrups, K., König, I. R., Cazier, J., Johansson, A., Hall, A. S., Lee, J., Willer, C. J., Chambers, J. C., Esko, T., Folkersen, L., Goel, A., Grundberg, E., Havulinna, A. S., Ho, W. K., Hopewell, J. C., Eriksson, N., Kleber, M. E., Kristiansson, K., Lundmark, P., Lyytikäinen, L., Rafelt, S., Shungin, D., Strawbridge, R. J., Thorleifsson, G., Tikkanen, E., Van Zuydam, N., Voight, B. F., Waite, L. L., Zhang, W., Ziegler, A., Absher, D., Altshuler, D., Balmforth, A. J., Barroso, I., Braund, P. S., Burgdorf, C., Claudi-Boehm, S., Cox, D., Dimitriou, M., Do, R., Doney, A. S., El Mokhtari, N., Eriksson, P., Fischer, K., Fontanillas, P., Franco-Cereceda, A., Gigante, B., Groop, L., Gustafsson, S., Hager, J., Hallmans, G., Han, B., Hunt, S. E., Kang, H. M., Illig, T., Kessler, T., Knowles, J. W., Kolovou, G., Kuusisto, J., Langenberg, C., Langford, C., Leander, K., Lokki, M., Lundmark, A., McCarthy, M. I., Meisinger, C., Melander, O., Mihailov, E., Maouche, S., Morris, A. D., Müller-Nurasyid, M., Nikus, K., Peden, J. F., Rayner, N. W., Rasheed, A., Rosinger, S., Rubin, D., Rumpf, M. P., Schäfer, A., Sivananthan, M., Song, C., Stewart, A. F., Tan, S., Thorgeirsson, G., van der Schoot, C. E., Wagner, P. J., Wells, G. A., Wild, P. S., Yang, T., Amouyel, P., Arveiler, D., Basart, H., Boehnke, M., Boerwinkle, E., Brambilla, P., Cambien, F., Cupples, A. L., de Faire, U., Dehghan, A., Diemert, P., Epstein, S. E., Evans, A., Ferrario, M. M., Ferrières, J., Gauguier, D., Go, A. S., Goodall, A. H., Gudnason, V., Hazen, S. L., Holm, H., Iribarren, C., Jang, Y., Kähönen, M., Kee, F., Kim, H., Klopp, N., Koenig, W., Kratzer, W., Kuulasmaa, K., Laakso, M., Laaksonen, R., Lee, J., Lind, L., Ouwehand, W. H., Parish, S., Park, J. E., Pedersen, N. L., Peters, A., Quertermous, T., Rader, D. J., Salomaa, V., Schadt, E., Shah, S. H., Sinisalo, J., Stark, K., Stefansson, K., Trégouët, D., Virtamo, J., Wallentin, L., Wareham, N., Zimmermann, M. E., Nieminen, M. S., Hengstenberg, C., Sandhu, M. S., Pastinen, T., Syvänen, A., Hovingh, G. K., Dedoussis, G., Franks, P. W., Lehtimäki, T., Metspalu, A., Zalloua, P. A., Siegbahn, A., Schreiber, S., Ripatti, S., Blankenberg, S. S., Perola, M., Clarke, R., Boehm, B. O., O'Donnell, C., Reilly, M. P., März, W., Collins, R., Kathiresan, S., Hamsten, A., Kooner, J. S., Thorsteinsdottir, U., Danesh, J., Palmer, C. N., Roberts, R., Watkins, H., Schunkert, H., Samani, N. J. 2013; 45 (1): 25-33

    Abstract

    Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

    View details for DOI 10.1038/ng.2480

    View details for PubMedID 23202125

  • Mendelian Randomization Studies Do Not Support a Causal Effect of Plasma Lipids on Insulin Sensitivity Fall, T., Xie, W., Hao, K., Arnlov, J., Abbasi, F., Schadt, E. E., Boran, G., Hansen, T., Greenawalt, D., Nolan, J. J., Pedersen, O., Haering, H., Ferrannini, E., Syvanen, A., Quertermous, T., Smith, U., Assimes, T. L., Laakso, M., Walker, M., Knowles, J. W., Weedon, M. N., Ingelsson, E., Frayling, T. M., GENESIS Investigators LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Exploring Predisposition and Treatment Response-the Promise of Genomics PROGRESS IN CARDIOVASCULAR DISEASES Pan, S., Knowles, J. W. 2012; 55 (1): 56-63

    Abstract

    Spurred by large-scale public and private efforts as well as technological developments, the last few years have seen a major leap forward in our understanding of the genetic basis of cardiovascular disease. This revolution is in its infancy and will continue to alter the medical landscape for years to come. There is a need within the general cardiology community to develop a better understanding about how these developments may alter routine clinical care. In this review, we will provide an overview of the current state of genetics as pertains to rare cardiovascular diseases and then review advances in the discovery of the genetic basis of common disease with the potential for improved risk assessment and drug development. We will also outline a few recent examples of pharmacogenetic advances that are already starting to become a part of clinical management and finally discuss the promise as well as the challenges in using next-generation sequencing technologies to provide personalized cardiovascular care.

    View details for DOI 10.1016/j.pcad.2012.04.006

    View details for Web of Science ID 000307087800007

    View details for PubMedID 22824110

  • Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS Knowles, J. W., Assimes, T. L., Kiernan, M., Pavlovic, A., Goldstein, B. A., Yank, V., McConnell, M. V., Absher, D., Bustamante, C., Ashley, E. A., Ioannidis, J. P. 2012; 5 (3): 368-376

    View details for DOI 10.1161/CIRCGENETICS.112.962746

    View details for PubMedID 22715281

  • The Evolution and Refinement of Traditional Risk Factors for Cardiovascular Disease CARDIOLOGY IN REVIEW deGoma, E. M., Knowles, J. W., Angeli, F., Budoff, M. J., Rader, D. J. 2012; 20 (3): 118-129

    Abstract

    Traditional risk factors for cardiovascular disease such as systemic hypertension and hypercholesterolemia, all described more than half a century ago, are relatively few in number. Efforts to expand the epidemiologic canon have met with limited success because of the high hurdle of causality. Fortunately, another solution to current deficiencies in risk assessment-in particular, the underestimation of risk both before and after initiation of pharmacotherapy-may exist. Parallel to the investigation of novel biomarkers, such as high-sensitivity C-reactive protein, ongoing research has yielded improved metrics of known causative conditions. This evolution of traditional risk factors, heralded by measures such as ambulatory blood pressure, central hemodynamics, low density lipoprotein particle concentration, genetic testing, and "vascular age," may better address the detection gap in cardiovascular disease.

    View details for DOI 10.1097/CRD.0b013e318239b924

    View details for Web of Science ID 000302772500004

    View details for PubMedID 22183062

    View details for PubMedCentralID PMC3310946

  • Use and overuse of left ventriculography AMERICAN HEART JOURNAL Witteles, R. M., Knowles, J. W., Perez, M., Morris, W. M., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. 2012; 163 (4): 617-?

    Abstract

    Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function.We performed a retrospective analysis of insurance claims data from the Aetna health care benefits database including all adults who underwent coronary angiography in 2007. The primary outcome was the concomitant use of left ventriculography during coronary angiography.Of 96,235 patients who underwent coronary angiography, left ventriculography was performed in 78,705 (81.8%). Use of left ventriculography was high in all subgroups, with greatest use in younger patients, those with a diagnosis of coronary disease, and those in the Southern United States. In the population who had undergone a very recent ejection fraction assessment by another modality (within 30 days) and who had had no intervening diagnosis of new heart failure, myocardial infarction, hypotension, or shock (37,149 patients), left ventriculography was performed in 32,798 patients (88%)-a rate higher than in the overall cohort.Left ventriculography was performed in most coronary angiography cases and often when an alternative imaging modality had been recently completed. New clinical practice guidelines should be considered to decrease the overuse of this invasive test.

    View details for DOI 10.1016/j.ahj.2011.12.018

    View details for PubMedID 22520528

  • Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies LANCET Sarwar, N., Butterworth, A. S., Freitag, D. F., Gregson, J., Willeit, P., Gorman, D. N., Gao, P., Saleheen, D., Rendon, A., Nelson, C. P., Braund, P. S., Hall, A. S., Chasman, D. I., Tybjaerg-Hansen, A., Chambers, J. C., Benjamin, E. J., Franks, P. W., Clarke, R., Wilde, A. A., Trip, M. D., Steri, M., Witteman, J. C., Qi, L., van der Schoot, C. E., de Faire, U., Erdmann, J., Stringham, H. M., Koenig, W., Rader, D. J., Melzer, D., Reich, D., Psaty, B. M., Kleber, M. E., Panagiotakos, D. B., Willeit, J., Wennberg, P., Woodward, M., Adamovic, S., Rimm, E. B., Meade, T. W., Gillum, R. F., Shaffer, J. A., Hofman, A., Onat, A., Sundstrom, J., Wassertheil-Smoller, S., Mellstrom, D., Gallacher, J., Cushman, M., Tracy, R. P., Kauhanen, J., Karlsson, M., Salonen, J. T., Wilhelmsen, L., Amouyel, P., Cantin, B., Best, L. G., Ben-Shlomo, Y., Manson, J. E., Davey-Smith, G., de Bakker, P. I., O'Donnell, C. J., Wilson, J. F., Wilson, A. G., Assimes, T. L., Jansson, J., Ohlsson, C., Tivesten, A., Ljunggren, O., Reilly, M. P., Hamsten, A., Ingelsson, E., Cambien, F., Hung, J., Thomas, G. N., Boehnke, M., Schunkert, H., Asselbergs, F. W., Kastelein, J. J., Gudnason, V., Salomaa, V., Harris, T. B., Kooner, J. S., Allin, K. H., Nordestgaard, B. G., Hopewell, J. C., Goodall, A. H., Ridker, P. M., Holm, H., Watkins, H., Ouwehand, W. H., Samani, N. J., Kaptoge, S., Di Angelantonio, E., Harari, O., Danesh, J. 2012; 379 (9822): 1205-1213

    Abstract

    Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

    View details for DOI 10.1016/S0140-6736(11)61931-4

    View details for Web of Science ID 000302230400033

    View details for PubMedID 22421339

  • Personalized Medicine and Cardiovascular Disease: From Genome to Bedside CURRENT CARDIOVASCULAR RISK REPORTS Pan, S., Dewey, F. E., Perez, M. V., Knowles, J. W., Chen, R., Butte, A. J., Ashley, E. A. 2011; 5 (6): 542–51
  • Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence PLOS GENETICS Dewey, F. E., Chen, R., Cordero, S. P., Ormond, K. E., Caleshu, C., Karczewski, K. J., Whirl-Carrillo, M., Wheeler, M. T., Dudley, J. T., Byrnes, J. K., Cornejo, O. E., Knowles, J. W., Woon, M., Sangkuhl, K., Gong, L., Thorn, C. F., Hebert, J. M., Capriotti, E., David, S. P., Pavlovic, A., West, A., Thakuria, J. V., Ball, M. P., Zaranek, A. W., Rehm, H. L., Church, G. M., West, J. S., Bustamante, C. D., Snyder, M., Altman, R. B., Klein, T. E., Butte, A. J., Ashley, E. A. 2011; 7 (9)

    Abstract

    Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

    View details for DOI 10.1371/journal.pgen.1002280

    View details for PubMedID 21935354

  • OVERUSE OF LEFT VENTRICULOGRAPHY 60th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) / I2 Summit / ACCF/Herman K. Gold Young Investigator's Award in Molecular and Cellular Cardiology Witteles, R., Knowles, J. W., Perez, M., Morris, W. H., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. ELSEVIER SCIENCE INC. 2011: E1289–E1289
  • Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease NATURE GENETICS Schunkert, H., Koenig, I. R., Kathiresan, S., Reilly, M. P., Assimes, T. L., Holm, H., Preuss, M., Stewart, A. F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S. S., Andersen, K., Anderson, J. L., Ardissino, D., Ball, S. G., Balmforth, A. J., Barnes, T. A., Becker, D. M., Becker, L. C., Berger, K., Bis, J. C., Boekholdt, S. M., Boerwinkle, E., Braund, P. S., Brown, M. J., Burnett, M. S., Buysschaert, I., Carlquist, J. F., Chen, L., Cichon, S., Codd, V., Davies, R. W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J. M., Diemert, P., Do, R., Doering, A., Eifert, S., El Mokhtari, N. E., Ellis, S. G., Elosua, R., Engert, J. C., Epstein, S. E., de Faire, U., Fischer, M., Folsom, A. R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J. R., Halperin, E., Hammond, N., Hazen, S. L., Hofman, A., Horne, B. D., Illig, T., Iribarren, C., Jones, G. T., Jukema, J. W., Kaiser, M. A., Kaplan, L. M., Kastelein, J. J., Khaw, K., Knowles, J. W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Lettre, G., Li, M., Lieb, W., Loley, C., Lotery, A. J., Mannucci, P. M., Maouche, S., Martinelli, N., McKeown, P. P., Meisinger, C., Meitinger, T., Melander, O., Merlini, P. A., Mooser, V., Morgan, T., Muehleisen, T. W., Muhlestein, J. B., Muenzel, T., Musunuru, K., Nahrstaedt, J., Nelson, C. P., Noethen, M. M., Olivieri, O., Patel, R. S., Patterson, C. C., Peters, A., Peyvandi, F., Qu, L., Quyyumi, A. A., Rader, D. J., Rallidis, L. S., Rice, C., Rosendaal, F. R., Rubin, D., Salomaa, V., Sampietro, M. L., Sandhu, M. S., Schadt, E., Schaefer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S. M., Siscovick, D. S., Sivananthan, M., Sivapalaratnam, S., Smith, A., Smith, T. B., Snoep, J. D., Soranzo, N., Spertus, J. A., Stark, K., Stirrups, K., Stoll, M., Tang, W. H., Tennstedt, S., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A. G., van Rij, A. M., Voight, B. F., Wareham, N. J., Wells, G. A., Wichmann, H., Wild, P. S., Willenborg, C., Witteman, J. C., Wright, B. J., Ye, S., Zeller, T., Ziegler, A., Cambien, F., Goodall, A. H., Cupples, L. A., Quertermous, T., Maerz, W., Hengstenberg, C., Blankenberg, S., Ouwehand, W. H., Hall, A. S., Deloukas, P., Thompson, J. R., Stefansson, K., Roberts, R., Thorsteinsdottir, U., O'Donnell, C. J., McPherson, R., Erdmann, J., Samani, N. J. 2011; 43 (4): 333-U153

    Abstract

    We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

    View details for DOI 10.1038/ng.784

    View details for Web of Science ID 000288903700013

    View details for PubMedID 21378990

    View details for PubMedCentralID PMC3119261

  • A Bivariate Genome-Wide Approach to Metabolic Syndrome STAMPEED Consortium DIABETES Kraja, A. T., Vaidya, D., Pankow, J. S., Goodarzi, M. O., Assimes, T. L., Kullo, I. J., Sovio, U., Mathias, R. A., Sun, Y. V., Franceschini, N., Absher, D., Li, G., Zhang, Q., Feitosa, M. F., Glazer, N. L., Haritunians, T., Hartikainen, A., Knowles, J. W., North, K. E., Iribarren, C., Kral, B., Yanek, L., O'Reilly, P. F., McCarthy, M. I., Jaquish, C., Couper, D. J., Chakravarti, A., Psaty, B. M., Becker, L. C., Province, M. A., Boerwinkle, E., Quertermous, T., Palotie, L., Jarvelin, M., Becker, D. M., Kardia, S. L., Rotter, J. I., Chen, Y. I., Borecki, I. B. 2011; 60 (4): 1329-1339

    Abstract

    OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

    View details for DOI 10.2337/db10-1011

    View details for Web of Science ID 000289496100029

    View details for PubMedID 21386085

    View details for PubMedCentralID PMC3064107

  • Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies LANCET Reilly, M. P., Li, M., He, J., Ferguson, J. F., Stylianou, I. M., Mehta, N. N., Burnett, M. S., Devaney, J. M., Knouff, C. W., Thompson, J. R., Horne, B. D., Stewart, A. F., Assimes, T. L., Wild, P. S., Allayee, H., Nitschke, P. L., Patel, R. S., Martinelli, N., Girelli, D., Quyyumi, A. A., Anderson, J. L., Erdmann, J., Hall, A. S., Schunkert, H., Quertermous, T., Blankenberg, S., Hazen, S. L., Roberts, R., Kathiresan, S., Samani, N. J., Epstein, S. E., Rader, D. J. 2011; 377 (9763): 383-392

    Abstract

    We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644).In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD.The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

    View details for DOI 10.1016/S0140-6736(10)61996-4

    View details for Web of Science ID 000287337000028

    View details for PubMedID 21239051

  • Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Assimes, T. L., Holm, H., Kathiresan, S., Reilly, M. P., Thorleifsson, G., Voight, B. F., Erdmann, J., Willenborg, C., Vaidya, D., Xie, C., Patterson, C. C., Morgan, T. M., Burnett, M. S., Li, M., Hlatky, M. A., Knowles, J. W., Thompson, J. R., Absher, D., Iribarren, C., Go, A., Fortmann, S. P., Sidney, S., Risch, N., Tang, H., Myers, R. M., Berger, K., Stoll, M., Shah, S. H., Thorgeirsson, G., Andersen, K., Havulinna, A. S., Herrera, J. E., Faraday, N., Kim, Y., Kral, B. G., Mathias, R. A., Ruczinski, I., Suktitipat, B., Wilson, A. F., Yanek, L. R., Becker, L. C., Linsel-Nitschke, P., Lieb, W., Koenig, I. R., Hengstenberg, C., Fischer, M., Stark, K., Reinhard, W., Winogradow, J., Grassl, M., Grosshennig, A., Preuss, M., Schreiber, S., Wichmann, H., Meisinger, C., Yee, J., Friedlander, Y., Do, R., Meigs, J. B., Williams, G., Nathan, D. M., MacRae, C. A., Qu, L., Wilensky, R. L., Matthai, W. H., Qasim, A. N., Hakonarson, H., Pichard, A. D., Kent, K. M., Satler, L., Lindsay, J. M., Waksman, R., Knouff, C. W., Waterworth, D. M., Walker, M. C., Mooser, V. E., Marrugat, J., Lucas, G., Subirana, I., Sala, J., Ramos, R., Martinelli, N., Olivieri, O., Trabetti, E., Malerba, G., Pignatti, P. F., Guiducci, C., Mirel, D., Parkin, M., Hirschhorn, J. N., Asselta, R., Duga, S., Musunuru, K., Daly, M. J., Purcell, S., Eifert, S., Braund, P. S., Wright, B. J., Balmforth, A. J., Ball, S. G., Ouwehand, W. H., Deloukas, P., Scholz, M., Cambien, F., Huge, A., Scheffold, T., Salomaa, V., Girelli, D., Granger, C. B., Peltonen, L., McKeown, P. P., Altshuler, D., Melander, O., Devaney, J. M., Epstein, S. E., Rader, D. J., Elosua, R., Engert, J. C., Anand, S. S., Hall, A. S., Ziegler, A., O'Donnell, C. J., Spertus, J. A., Siscovick, D., Schwartz, S. M., Becker, D., Thorsteinsdottir, U., Stefansson, K., Schunkert, H., Samani, N. J., Quertermous, T. 2010; 56 (19): 1552-1563

    Abstract

    We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups.The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

    View details for DOI 10.1016/j.jacc.2010.06.022

    View details for PubMedID 20933357

  • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index NATURE GENETICS Speliotes, E. K., Willer, C. J., Berndt, S. I., Monda, K. L., Thorleifsson, G., Jackson, A. U., Allen, H. L., Lindgren, C. M., Luan, J., Maegi, R., Randall, J. C., Vedantam, S., Winkler, T. W., Qi, L., Workalemahu, T., Heid, I. M., Steinthorsdottir, V., Stringham, H. M., Weedon, M. N., Wheeler, E., Wood, A. R., Ferreira, T., Weyant, R. J., Segre, A. V., Estrada, K., Liang, L., Nemesh, J., Park, J., Gustafsson, S., Kilpelaenen, T. O., Yang, J., Bouatia-Naji, N., Esko, T., Feitosa, M. F., Kutalik, Z., Mangino, M., Raychaudhuri, S., Scherag, A., Smith, A. V., Welch, R., Zhao, J. H., Aben, K. K., Absher, D. M., Amin, N., Dixon, A. L., Fisher, E., Glazer, N. L., Goddard, M. E., Heard-Costa, N. L., Hoesel, V., Hottenga, J., Johansson, A., Johnson, T., Ketkar, S., Lamina, C., Li, S., Moffatt, M. F., Myers, R. H., Narisu, N., Perry, J. R., Peters, M. J., Preuss, M., Ripatti, S., Rivadeneira, F., Sandholt, C., Scott, L. J., Timpson, N. J., Tyrer, J. P., van Wingerden, S., Watanabe, R. M., White, C. C., Wiklund, F., Barlassina, C., Chasman, D. I., Cooper, M. N., Jansson, J., Lawrence, R. W., Pellikka, N., Prokopenko, I., Shi, J., Thiering, E., Alavere, H., Alibrandi, M. T., Almgren, P., Arnold, A. M., Aspelund, T., Atwood, L. D., Balkau, B., Balmforth, A. J., Bennett, A. J., Ben-Shlomo, Y., Bergman, R. N., Bergmann, S., Biebermann, H., Blakemore, A. I., Boes, T., Bonnycastle, L. L., Bornstein, S. R., Brown, M. J., Buchanan, T. A., Busonero, F., Campbell, H., Cappuccio, F. P., Cavalcanti-Proenca, C., Chen, Y. I., Chen, C., Chines, P. S., Clarke, R., Coin, L., Connell, J., Day, I. N., den Heijer, M., Duan, J., Ebrahim, S., Elliott, P., Elosua, R., Eiriksdottir, G., Erdos, M. R., Eriksson, J. G., Facheris, M. F., Felix, S. B., Fischer-Posovszky, P., Folsom, A. R., Friedrich, N., Freimer, N. B., Fu, M., Gaget, S., Gejman, P. V., Geus, E. J., Gieger, C., Gjesing, A. P., Goel, A., Goyette, P., Grallert, H., Graessler, J., Greenawalt, D. M., Groves, C. J., Gudnason, V., Guiducci, C., Hartikainen, A., Hassanali, N., Hall, A. S., Havulinna, A. S., Hayward, C., Heath, A. C., Hengstenberg, C., Hicks, A. A., Hinney, A., Hofman, A., Homuth, G., Hui, J., Igl, W., Iribarren, C., Isomaa, B., Jacobs, K. B., Jarick, I., Jewell, E., John, U., Jorgensen, T., Jousilahti, P., Jula, A., Kaakinen, M., Kajantie, E., Kaplan, L. M., Kathiresan, S., Kettunen, J., Kinnunen, L., Knowles, J. W., Kolcic, I., Koenig, I. R., Koskinen, S., Kovacs, P., Kuusisto, J., Kraft, P., Kvaloy, K., Laitinen, J., Lantieri, O., Lanzani, C., Launer, L. J., Lecoeur, C., Lehtimaeki, T., Lettre, G., Liu, J., Lokki, M., Lorentzon, M., Luben, R. N., Ludwig, B., Manunta, P., Marek, D., Marre, M., Martin, N. G., McArdle, W. L., McCarthy, A., McKnight, B., Meitinger, T., Melander, O., Meyre, D., Midthjell, K., Montgomery, G. W., Morken, M. A., Morris, A. P., Mulic, R., Ngwa, J. S., Nelis, M., Neville, M. J., Nyholt, D. R., O'Donnell, C. J., O'Rahilly, S., Ong, K. K., Oostra, B., Pare, G., Parker, A. N., Perola, M., Pichler, I., Pietilaeinen, K. H., Platou, C. G., Polasek, O., Pouta, A., Rafelt, S., Raitakari, O., Rayner, N. W., Ridderstrale, M., Rief, W., Ruokonen, A., Robertson, N. R., Rzehak, P., Salomaa, V., Sanders, A. R., Sandhu, M. S., Sanna, S., Saramies, J., Savolainen, M. J., Scherag, S., Schipf, S., Schreiber, S., Schunkert, H., Silander, K., Sinisalo, J., Siscovick, D. S., Smit, J. H., Soranzo, N., Sovio, U., Stephens, J., Surakka, I., Swift, A. J., Tammesoo, M., Tardif, J., Teder-Laving, M., Teslovich, T. M., Thompson, J. R., Thomson, B., Toenjes, A., Tuomi, T., van Meurs, J. B., van Ommen, G., Vatin, V., Viikari, J., Visvikis-Siest, S., Vitart, V., Vogel, C. I., Voight, B. F., Waite, L. L., Wallaschofski, H., Walters, G. B., Widen, E., Wiegand, S., Wild, S. H., Willemsen, G., Witte, D. R., Witteman, J. C., Xu, J., Zhang, Q., Zgaga, L., Ziegler, A., Zitting, P., Beilby, J. P., Farooqi, I. S., Hebebrand, J., Huikuri, H. V., James, A. L., Kaehoenen, M., Levinson, D. F., Macciardi, F., Nieminen, M. S., Ohlsson, C., Palmer, L. J., Ridker, P. M., Stumvoll, M., Beckmann, J. S., Boeing, H., Boerwinkle, E., Boomsma, D. I., Caulfield, M. J., Chanock, S. J., Collins, F. S., Cupples, L. A., Smith, G. D., Erdmann, J., Froguel, P., Greonberg, H., Gyllensten, U., Hall, P., Hansen, T., Harris, T. B., Hattersley, A. T., Hayes, R. B., Heinrich, J., Hu, F. B., Hveem, K., Illig, T., Jarvelin, M., Kaprio, J., Karpe, F., Khaw, K., Kiemeney, L. A., Krude, H., Laakso, M., Lawlor, D. A., Metspalu, A., Munroe, P. B., Ouwehand, W. H., Pedersen, O., Penninx, B. W., Peters, A., Pramstaller, P. P., Quertermous, T., Reinehr, T., Rissanen, A., Rudan, I., Samani, N. J., Schwarz, P. E., Shuldiner, A. R., Spector, T. D., Tuomilehto, J., Uda, M., Uitterlinden, A., Valle, T. T., Wabitsch, M., Waeber, G., Wareham, N. J., Watkins, H., Wilson, J. F., Wright, A. F., Zillikens, M. C., Chatterjee, N., McCarroll, S. A., Purcell, S., Schadt, E. E., Visscher, P. M., Assimes, T. L., Borecki, I. B., Deloukas, P., Fox, C. S., Groop, L. C., Haritunians, T., Hunter, D. J., Kaplan, R. C., Mohlke, K. L., O'Connell, J. R., Peltonen, L., Schlessinger, D., Strachan, D. P., van Duijn, C. M., Wichmann, H., Frayling, T. M., Thorsteinsdottir, U., Abecasis, G. R., Barroso, I., Boehnke, M., Stefansson, K., North, K. E., McCarthy, M. I., Hirschhorn, J. N., Ingelsson, E., Loos, R. J. 2010; 42 (11): 937-U53

    Abstract

    Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

    View details for DOI 10.1038/ng.686

    View details for Web of Science ID 000283540500010

    View details for PubMedID 20935630

  • Hundreds of variants clustered in genomic loci and biological pathways affect human height NATURE Allen, H. L., Estrada, K., Lettre, G., Berndt, S. I., Weedon, M. N., Rivadeneira, F., Willer, C. J., Jackson, A. U., Vedantam, S., Raychaudhuri, S., Ferreira, T., Wood, A. R., Weyant, R. J., Segre, A. V., Speliotes, E. K., Wheeler, E., Soranzo, N., Park, J., Yang, J., Gudbjartsson, D., Heard-Costa, N. L., Randall, J. C., Qi, L., Smith, A. V., Maegi, R., Pastinen, T., Liang, L., Heid, I. M., Luan, J., Thorleifsson, G., Winkler, T. W., Goddard, M. E., Lo, K. S., Palmer, C., Workalemahu, T., Aulchenko, Y. S., Johansson, A., Zillikens, M. C., Feitosa, M. F., Esko, T., Johnson, T., Ketkar, S., Kraft, P., Mangino, M., Prokopenko, I., Absher, D., Albrecht, E., Ernst, F., Glazer, N. L., Hayward, C., Hottenga, J., Jacobs, K. B., Knowles, J. W., Kutalik, Z., Monda, K. L., Polasek, O., Preuss, M., Rayner, N. W., Robertson, N. R., Steinthorsdottir, V., Tyrer, J. P., Voight, B. F., Wiklund, F., Xu, J., Zhao, J. H., Nyholt, D. R., Pellikka, N., Perola, M., Perry, J. R., Surakka, I., Tammesoo, M., Altmaier, E. L., Amin, N., Aspelund, T., Bhangale, T., Boucher, G., Chasman, D. I., Chen, C., Coin, L., Cooper, M. N., Dixon, A. L., Gibson, Q., Grundberg, E., Hao, K., Junttila, M. J., Kaplan, L. M., Kettunen, J., Koenig, I. R., Kwan, T., Lawrence, R. W., Levinson, D. F., Lorentzon, M., McKnight, B., Morris, A. P., Mueller, M., Ngwa, J. S., Purcell, S., Rafelt, S., Salem, R. M., Salvi, E., Sanna, S., Shi, J., Sovio, U., Thompson, J. R., Turchin, M. C., Vandenput, L., Verlaan, D. J., Vitart, V., White, C. C., Ziegler, A., Almgren, P., Balmforth, A. J., Campbell, H., Citterio, L., de Grandi, A., Dominiczak, A., Duan, J., Elliott, P., Elosua, R., Eriksson, J. G., Freimer, N. B., Geus, E. J., Glorioso, N., Haiqing, S., Hartikainen, A., Havulinna, A. S., Hicks, A. A., Hui, J., Igl, W., Illig, T., Jula, A., Kajantie, E., Kilpelaeinen, T. O., Koiranen, M., Kolcic, I., Koskinen, S., Kovacs, P., Laitinen, J., Liu, J., Lokki, M., Marusic, A., Maschio, A., Meitinger, T., Mulas, A., Pare, G., Parker, A. N., Peden, J. F., Petersmann, A., Pichler, I., Pietilainen, K. H., Pouta, A., Riddertrale, M., Rotter, J. I., Sambrook, J. G., Sanders, A. R., Schmidt, C. O., Sinisalo, J., Smit, J. H., Stringham, H. M., Walters, G. B., Widen, E., Wild, S. H., Willemsen, G., Zagato, L., Zgaga, L., Zitting, P., Alavere, H., Farrall, M., McArdle, W. L., Nelis, M., Peters, M. J., Ripatti, S., vVan Meurs, J. B., Aben, K. K., Ardlie, K. G., Beckmann, J. S., Beilby, J. P., Bergman, R. N., Bergmann, S., Collins, F. S., Cusi, D., den Heijer, M., Eiriksdottir, G., Gejman, P. V., Hall, A. S., Hamsten, A., Huikuri, H. V., Iribarren, C., Kahonen, M., Kaprio, J., Kathiresan, S., Kiemeney, L., Kocher, T., Launer, L. J., Lehtimaki, T., Melander, O., Mosley, T. H., Musk, A. W., Nieminen, M. S., O'Donnell, C. J., Ohlsson, C., Oostra, B., Palmer, L. J., Raitakari, O., Ridker, P. M., Rioux, J. D., Rissanen, A., Rivolta, C., Schunkert, H., Shuldiner, A. R., Siscovick, D. S., Stumvoll, M., Toenjes, A., Tuomilehto, J., van Ommen, G., Viikari, J., Heath, A. C., Martin, N. G., Montgomery, G. W., Province, M. A., Kayser, M., Arnold, A. M., Atwood, L. D., Boerwinkle, E., Chanock, S. J., Deloukas, P., Gieger, C., Gronberg, H., Hall, P., Hattersley, A. T., Hengstenberg, C., Hoffman, W., Lathrop, G. M., Salomaa, V., Schreiber, S., Uda, M., Waterworth, D., Wright, A. F., Assimes, T. L., Barroso, I., Hofman, A., Mohlke, K. L., Boomsma, D. I., Caulfield, M. J., Cupples, L. A., Erdmann, J., Fox, C. S., Gudnason, V., Gyllensten, U., Harris, T. B., Hayes, R. B., Jarvelin, M., Mooser, V., Munroe, P. B., Ouwehand, W. H., Penninx, B. W., Pramstaller, P. P., Quertermous, T., Rudan, I., Samani, N. J., Spector, T. D., Voelzke, H., Watkins, H., Wilson, J. F., Groop, L. C., Haritunians, T., Hu, F. B., Kaplan, R. C., Metspalu, A., North, K. E., Schlessinger, D., Wareham, N. J., Hunter, D. J., O'Connell, J. R., Strachan, D. P., Schadt, H., Thorsteinsdottir, U., Peltonen, L., Uitterlinden, A. G., Visscher, P. M., Chatterjee, N., Loos, R. J., Boehnke, M., McCarthy, M. I., Ingelsson, E., Lindgren, C. M., Abecasis, G. R., Stefansson, K., Frayling, T. M., Hirschhorn, J. N. 2010; 467 (7317): 832-838

    Abstract

    Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

    View details for DOI 10.1038/nature09410

    View details for Web of Science ID 000282898700065

    View details for PubMedID 20881960

  • Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans 59th Annual Meeting of the American-Society-of-Human-Genetics Ingelsson, E., Langenberg, C., Hivert, M., Prokopenko, I., Lyssenko, V., Dupuis, J., Maegi, R., Sharp, S., Jackson, A. U., Assimes, T. L., Shrader, P., Knowles, J. W., Zethelius, B., Abbasi, F. A., Bergman, R. N., Bergmann, A., Berne, C., Boehnke, M., Bonnycastle, L. L., Bornstein, S. R., Buchanan, T. A., Bumpstead, S. J., Boettcher, Y., Chines, P., Collins, F. S., Cooper, C. C., Dennison, E. M., Erdos, M. R., Ferrannini, E., Fox, C. S., Graessler, J., Hao, K., Isomaa, B., Jameson, K. A., Kovacs, P., Kuusisto, J., Laakso, M., Ladenval, C., Mohlke, K. L., Morken, M. A., Narisu, N., Nathan, D. M., Pascoe, L., Payne, F., Petrie, J. R., Sayer, A. A., Schwarz, P. E., Scott, L. J., Stringham, H. M., Stumvoll, M., Swift, A. J., Syvanen, A., Tuomi, T., Tuomilehto, J., Tonjes, A., Valle, T. T., Williams, G. H., Lind, L., Barroso, I., Quertermous, T., Walker, M., Wareham, N. J., Meigs, J. B., McCarthy, M. I., Groop, L., Watanabe, R. M., Florez, J. C. AMER DIABETES ASSOC. 2010: 1266–75

    Abstract

    OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

    View details for DOI 10.2337/DB09-1568

    View details for Web of Science ID 000277554700019

    View details for PubMedID 20185807

    View details for PubMedCentralID PMC2857908

  • Genome-wide meta-analyses identify multiple loci associated with smoking behavior NATURE GENETICS Furberg, H., Kim, Y., Dackor, J., Boerwinkle, E., Franceschini, N., Ardissino, D., Bernardinelli, L., Mannucci, P. M., Mauri, F., Merlini, P. A., Absher, D., Assimes, T. L., Fortmann, S. P., Iribarren, C., Knowles, J. W., Quertermous, T., Ferrucci, L., Tanaka, T., Bis, J. C., Furberg, C. D., Haritunians, T., McKnight, B., Psaty, B. M., Taylor, K. D., Thacker, E. L., Almgren, P., Groop, L., Ladenvall, C., Boehnke, M., Jackson, A. U., Mohlke, K. L., Stringham, H. M., Tuomilehto, J., Benjamin, E. J., Hwang, S., Levy, D., Preis, S. R., Vasan, R. S., Duan, J., Gejman, P. V., Levinson, D. F., Sanders, A. R., Shi, J., Lips, E. H., McKay, J. D., Agudo, A., Barzan, L., Bencko, V., Benhamou, S., Castellsague, X., Canova, C., Conway, D. I., Fabianova, E., Foretova, L., Janout, V., Healy, C. M., Holcatova, I., Kjaerheim, K., Lagiou, P., Lissowska, J., Lowry, R., Macfarlane, T. V., Mates, D., Richiardi, L., Rudnai, P., Szeszenia-Dabrowska, N., Zaridze, D., Znaor, A., Lathrop, M., Brennan, P., Bandinelli, S., Frayling, T. M., Guralnik, J. M., Milaneschi, Y., Perry, J. R., Altshuler, D., Elosua, R., Kathiresan, S., Lucas, G., Melander, O., O'Donnell, C. J., Salomaa, V., Schwartz, S. M., Voight, B. F., Penninx, B. W., Smit, J. H., Vogelzangs, N., Boomsma, D. I., de Geus, E. J., Vink, J. M., Willemsen, G., Chanock, S. J., Gu, F., Hankinson, S. E., Hunter, D. J., Hofman, A., Tiemeier, H., Uitterlinden, A. G., van Duijn, C. M., Walter, S., Chasman, D. I., Everett, B. M., Pare, G., Ridker, P. M., Li, M. D., Maes, H. H., Audrain-McGovern, J., Posthuma, D., Thornton, L. M., Lerman, C., Kaprio, J., Rose, J. E., Ioannidis, J. P., Kraft, P., Lin, D., Sullivan, P. F. 2010; 42 (5): 441-U134

    Abstract

    Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

    View details for DOI 10.1038/ng.571

    View details for Web of Science ID 000277179500017

    View details for PubMedID 20418890

    View details for PubMedCentralID PMC2914600

  • Clinical assessment incorporating a personal genome LANCET Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., Pushkarev, D., Neff, N. F., Hudgins, L., Gong, L., Hodges, L. M., Berlin, D. S., Thorn, C. F., Sangkuhl, K., Hebert, J. M., Woon, M., Sagreiya, H., Whaley, R., Knowles, J. W., Chou, M. F., Thakuria, J. V., Rosenbaum, A. M., Zaranek, A. W., Church, G. M., Greely, H. T., Quake, S. R., Altman, R. B. 2010; 375 (9725): 1525-1535

    Abstract

    The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.

    View details for Web of Science ID 000277655100025

    View details for PubMedID 20435227

  • Characterizing the admixed African ancestry of African Americans GENOME BIOLOGY Zakharia, F., Basu, A., Absher, D., Assimes, T. L., Go, A. S., Hlatky, M. A., Iribarren, C., Knowles, J. W., Li, J., Narasimhan, B., Sidney, S., Southwick, A., Myers, R. M., Quertermous, T., Risch, N., Tang, H. 2009; 10 (12)

    Abstract

    Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.

    View details for DOI 10.1186/gb-2009-10-12-r141

    View details for Web of Science ID 000274289000011

    View details for PubMedID 20025784

    View details for PubMedCentralID PMC2812948

  • Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study HUMAN MOLECULAR GENETICS Assimes, T. L., Knowles, J. W., Basu, A., Iribarren, C., Southwick, A., Tang, H., Absher, D., Li, J., Fair, J. M., Rubin, G. D., Sidney, S., Fortmann, S. P., Go, A. S., Hlatky, M. A., Myers, R. M., Risch, N., Quertermous, T. 2008; 17 (15): 2320-2328

    Abstract

    A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.

    View details for DOI 10.1093/hmg/ddn132

    View details for Web of Science ID 000257788300007

    View details for PubMedID 18443000

    View details for PubMedCentralID PMC2733811

  • A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease ATHEROSCLEROSIS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Borchert, A., Volcik, K. A., Grove, M. L., Tabor, H. K., Southwick, A., Tabibiazar, R., Sidney, S., Boerwinkle, E., Go, A. S., Iribarren, C., Hlatky, M. A., Fortmann, S. P., Myers, R. M., Kuhn, H., Riseh, N., Quertermous, T. 2008; 198 (1): 136-144

    Abstract

    Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9).A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.

    View details for DOI 10.1016/j.atheroscierosis.2007.09.003

    View details for Web of Science ID 000255491800016

    View details for PubMedID 17959182

    View details for PubMedCentralID PMC2440699

  • Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease HUMAN GENETICS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Volcik, K. A., Southwick, A., Tabor, H. K., Hartiala, J., Allayee, H., Grove, M. L., Tabibiazar, R., Sidney, S., Fortmann, S. P., Go, A., Hlatky, M., Iribarren, C., Boerwinkle, E., Myers, R., Risch, N., Quertermous, T. 2008; 123 (4): 399-408

    Abstract

    Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.

    View details for DOI 10.1007/s00439-008-0489-5

    View details for Web of Science ID 000254959600008

    View details for PubMedID 18369664

  • Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLRI) with CAD BMC MEDICAL GENETICS Knowles, J. W., Assimes, T. L., Boerwinkle, E., Fortmann, S. P., Go, A., Grove, M. L., Hlatky, M., Iribarren, C., Li, J., Myers, R., Risch, N., Sidney, S., Southwick, A., Volcik, K. A., Quertermous, T. 2008; 9

    Abstract

    The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in OLR1 are associated with clinically significant CAD in the Atherosclerotic Disease, VAscular FuNction, & Geneti C Epidemiology (ADVANCE) study.ADVANCE is a population-based case-control study of subjects receiving care within Kaiser Permanente of Northern California including a subset of participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We first resequenced the promoter, exonic, and splice site regions of OLR1 and then genotyped four single nucleotide polymorphisms (SNPs), including a non-synonymous SNP (rs11053646, Lys167Asn) as well as an intronic SNP (rs3736232) previously associated with CAD.In 1,809 cases with clinical CAD and 1,734 controls, the minor allele of the coding SNP was nominally associated with a lower odds ratio (OR) of CAD across all ethnic groups studied (minimally adjusted OR 0.8, P = 0.007; fully adjusted OR 0.8, P = 0.01). The intronic SNP was nominally associated with an increased risk of CAD (minimally adjusted OR 1.12, p = 0.03; fully adjusted OR 1.13, P = 0.03). However, these associations were not replicated in over 13,200 individuals (including 1,470 cases) in the Atherosclerosis Risk in Communities (ARIC) study.Our results do not support the presence of an association between selected common SNPs in OLR1 and the risk of clinical CAD.

    View details for DOI 10.1186/1471-2350-9-23

    View details for Web of Science ID 000255652400001

    View details for PubMedID 18384690

    View details for PubMedCentralID PMC2322963

  • Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Wheeler, M. T., Ho, M., Knowles, J. W., Pavlovic, A., Ashley, E. A. 2008; 1 (1): 25-36

    Abstract

    Heart failure is a significant medical problem affecting more than five million people in the USA alone. Although clinical trials of pharmacological agents have demonstrated significant reductions in the relative risk of mortality across populations, absolute mortality remains high. In addition, individual variation in response is great. Some of this variation may be explained by genetic polymorphism. In this paper, we review the key studies to date in heart failure pharmacogenetics, setting this against a background of recent progress in the genetics of warfarin metabolism. Several polymorphisms that have supporting molecular and clinical data in the heart failure literature are reviewed, among them the beta1-adrenergic receptor variant Arg389Gly and the angiotensin converting enzyme gene insertion/deletion polymorphism. These variants and others are responsible for a fraction of the total variation seen in the treatment response to heart failure. With the dawn of the genomic age, further pharmacogenetic and new pharmacogenomic studies will advance our ability to tailor the treatment of heart failure.

    View details for DOI 10.1007/s12265-007-9007-8

    View details for Web of Science ID 000207734400008

    View details for PubMedID 20559955

  • Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction AMERICAN HEART JOURNAL Knowles, J. W., Wang, H., Itakura, H., Southwick, A., Myers, R. M., Iribarren, C., Fortmann, S. P., Go, A. S., Quertermous, T., Hlatky, M. A. 2007; 154 (6): 1052-1058

    Abstract

    Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis.We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina.An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively).Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.

    View details for DOI 10.1016/j.ahj.2007.05.021

    View details for PubMedID 18035074

  • Genetic susceptibility to peripheral arterial disease: A dark corner in vascular biology ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Knowles, J. W., Assimes, T. L., Li, J., Quertermous, T., Cooke, J. P. 2007; 27 (10): 2068-2078

    Abstract

    Peripheral arterial disease (PAD) is characterized by reduced blood flow to the limbs, usually as a consequence of atherosclerosis, and affects approximately 12 million Americans. It is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. Similar to other atherosclerotic diseases, such as coronary artery disease, PAD is the result of the complex interplay between injurious environmental stimuli and genetic predisposing factors of the host. Genetic susceptibility to PAD is likely contributed by sequence variants in multiple genes, each with modest effects. Although many of these variants probably alter susceptibility both to PAD and to coronary artery disease, it is likely that there exists a set of variants specifically to alter susceptibility to PAD. Despite the prevalence of PAD and its high societal burden, relatively little is known about such genetic variants. This review summarizes our limited present knowledge and gives an overview of recent, more powerful approaches to elucidating the genetic basis of PAD. We discuss the advantages and limitations of genetic studies and highlight the need for collaborative networks of PAD investigators for shedding light on this dark corner of vascular biology.

    View details for DOI 10.1161/01.ATV.0000282199.66398.8c

    View details for Web of Science ID 000249587000002

    View details for PubMedID 17656669

    View details for PubMedCentralID PMC4321902

  • A case of complete heart block reverting to normal sinus rhythm after treatment for cardiac invasive Burkitt's lymphoma ANNALS OF HEMATOLOGY Knowles, J. W., Elliott, A. B., Brody, J. 2007; 86 (9): 687-690

    View details for DOI 10.1007/s00277-007-0290-x

    View details for Web of Science ID 000248580400011

    View details for PubMedID 17410366

  • Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Caron, K. M., James, L. R., Kim, H. S., Knowles, J., Uhlir, R., Mao, L., Hagaman, J. R., Cascio, W., Rockman, H., Smithies, O. 2004; 101 (9): 3106-3111

    Abstract

    Several mouse models have already proved valuable for investigating hypertrophic responses to cardiac stress. Here, we characterize one caused by a well defined single copy transgene, RenTgMK, that genetically clamps plasma renin and thence angiotensin II at high levels. All of the transgenic males develop concentric cardiac hypertrophy with fibrosis but without dilatation. Over half die suddenly aged 6-8 months. Telemetry showed disturbances in diurnal rhythms a few days before death and, later, electrocardiographic disturbances comparable to those in humans with congestive heart failure. Expression of seven hypertrophy-related genes in this and two categorically different models (lack of atrial natriuretic peptide receptor A; overexpression of calsequestrin) were compared. Statistical analyses show that ventricular expressions of the genes coding for atrial natriuretic peptide, beta myosin heavy chain, medium chain acyl-CoA dehydrogenase, and adrenomedullin correlate equally well with the degree of hypertrophy, although their ranges of expression are, respectively, 50-, 30-, 10-, and 3-fold.

    View details for DOI 10.1073/pnas.0307333101

    View details for Web of Science ID 000220065300082

    View details for PubMedID 14978280

  • Increased atherosclerosis and smooth muscle cell hypertrophy in natriuretic peptide receptor A(-/-) apolipoprotein E-/- mice ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Alexander, M. R., Knowles, J. W., Nishikimi, T., Maeda, N. 2003; 23 (6): 1077-1082

    Abstract

    Natriuretic peptide signaling is important in the regulation of blood pressure as well as in the growth of multiple cell types. To examine the role of natriuretic peptide signaling in atherosclerosis, we crossbred mice that lack natriuretic peptide receptor A (NPRA; Npr1-/-) with atherosclerosis-prone mice that lack apolipoprotein E (apoE; Apoe-/-).Doubly deficient Npr1-/-Apoe-/- mice have increased blood pressure relative to Npr1+/+Apoe-/- mice (118+/-4 mm Hg compared with 108+/-2 mm Hg, P<0.05) that is coincident with a 64% greater atherosclerotic lesion size (P<0.005) and more advanced plaque morphology. Additionally, aortic medial thickness is increased by 52% in Npr1-/-Apoe-/- mice relative to Npr1+/+Apoe-/- mice (P<0.0001). Npr1-/-Apoe-/- mice also have significantly greater cardiac mass (9.0+/-0.3 mg/g body weight) than either Npr1+/+Apoe-/- mice (5.8+/-0.2 mg/g) or Npr1-/-Apoe+/+ mice (7.1+/-0.2 mg/g), suggesting that the lack of both NPRA and apoE synergistically enhances cardiac hypertrophy.These data provide evidence that NPR1 is an atherosclerosis susceptibility locus and represents a potential link between atherosclerosis and cardiac hypertrophy. Our results also suggest roles for Npr1 as well as Apoe in regulation of hypertrophic cell growth.

    View details for DOI 10.1161/01.ATV.0000071702.45741.2E

    View details for Web of Science ID 000183527900025

    View details for PubMedID 12702516

  • Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects HUMAN GENETICS Knowles, J. W., Erickson, L. M., Guy, V. K., Sigel, C. S., Wilder, J. C., Maeda, N. 2003; 112 (1): 62-70

    Abstract

    Genetic susceptibility to common conditions, such as essential hypertension and cardiac hypertrophy, is probably determined by various combinations of small quantitative changes in the expression of many genes. NPR1, coding for natriuretic peptide receptor A (NPRA), is a potential candidate, because NPRA mediates natriuretic, diuretic, and vasorelaxing actions of the nariuretic peptides, and because genetically determined quantitative changes in the expression of this gene affect blood pressure and heart weight in a dose-dependent manner in mice. To determine whether there are common quantitative variants in human NPR1, we have sequenced the entire human NPR1 gene and identified 10 polymorphic sites in its non-coding sequence by using DNA from 34 unrelated human individuals. Five of the sites are single nucleotide polymorphisms; the remaining five are length polymorphisms, including a highly variable complex dinucleotide repeat in intron 19. There are three common haplotypes 5' to this dinucleotide repeat and three 3' to it, but the 5' haplotypes and 3' haplotypes appear to be randomly associated. Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequences of NPR1 and its 3' untranslated regions showed that these polymorphisms have functional effects. We conclude that common NPR1 alleles can alter expression of the gene as much as two-fold and could therefore significantly affect genetic risks for essential hypertension and cardiac hypertrophy in humans.

    View details for DOI 10.1007/s00439-002-0834-z

    View details for Web of Science ID 000180552400010

    View details for PubMedID 12483301

  • Ventricular expression of natriuretic peptides in Npr1(-/-) mice with cardiac hypertrophy and fibrosis AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Ellmers, L. J., Knowles, J. W., Kim, H. S., Smithies, O., Maeda, N., Cameron, V. A. 2002; 283 (2): H707-H714

    Abstract

    Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and volume, and exert their biological actions via the natriuretic peptide receptor-A gene (Npr1). Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure. This study examined the relationships between ANP and BNP gene expression, immunoreactivity and fibrosis in cardiac tissue, circulating ANP levels, and ANP and BNP mRNA during embryogenesis in Npr1(-/-) mice. Disruption of the Npr1 signaling pathway resulted in augmented ANP and BNP gene and ANP protein expression in the cardiac ventricles, most pronounced for ANP mRNA in females [414 +/- 57 in Npr1(-/-) ng/mg and 124 +/- 25 ng/mg in wild-type (WT) by Taqman assay, P < 0.001]. This increased expression was highly correlated to the degree of cardiac hypertrophy and was localized to the left ventricle (LV) inner free wall and to areas of ventricular fibrosis. In contrast, plasma ANP was significantly greater than WT in male but not female Npr1(-/-) mice. Increased ANP and BNP gene expression was observed in Npr1(-/-) embryos from 16 days of gestation. Our study suggests that cardiac ventricular expression of ANP and BNP is more closely associated with local hypertrophy and fibrosis than either systemic blood pressure or circulating ANP levels.

    View details for DOI 10.1152/ajpheart.00677.2001

    View details for Web of Science ID 000176880500031

    View details for PubMedID 12124219

  • Interactions between endothelial nitric oxide synthase and sex hormones in vascular protection in mice JOURNAL OF CLINICAL INVESTIGATION Hodgin, J. B., Knowles, J. W., Kim, H. S., Smithies, O., Maeda, N. 2002; 109 (4): 541-548

    Abstract

    The vasculoprotective effects of sex hormones, particularly estrogens, have been attributed to their ability to increase the bioavailability of nitric oxide through activation of endothelial nitric oxide synthase (eNOS). To dissect the relative contribution in vivo of eNOS, sex hormones, and their interaction in two complex vascular phenotypes, hypertension and atherosclerosis, we used mice doubly deficient in eNOS and apoE (nnee) or lacking only apoE (NNee). Females and males were gonadectomized at 1 month of age and implanted either with control pellets or pellets releasing 17beta-estradiol (E2). Hormonally intact nnee mice have elevated blood pressure (BP) and increased atherosclerosis compared with NNee mice, but on removal of gonads, BP and atherosclerosis decreased significantly in nnee mice but not in NNee mice. Three months of treatment with exogenous E2 dramatically reduced atherosclerosis and significantly lowered BP in both NNee and nnee mice compared with animals treated with control pellets. Thus exogenous E2 has strong BP-lowering and atheroprotective effects in apoE-deficient mice, but eNOS is not essential for either effect. Endogenous sex hormones, on the other hand, cause significant damage to the vasculature in the absence of eNOS, but these effects are overridden by interactions between eNOS and sex hormones.

    View details for DOI 10.1172/JC1200214066

    View details for Web of Science ID 000173965900016

    View details for PubMedID 11854327

  • Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide BIOCHEMICAL JOURNAL Goy, M. F., Oliver, P. M., Purdy, K. E., Knowles, J. W., Fox, J. E., Mohler, P. J., Qian, X., Smithies, O., Maeda, N. 2001; 358: 379-387

    Abstract

    Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert their physiological actions by binding to natriuretic peptide receptor A (NPRA), a receptor guanylate cyclase (rGC) that synthesizes cGMP in response to both ligands. The family of rGCs is rapidly expanding, and it is plausible that there might be additional, as yet undiscovered, rGCs whose function is to provide alternative signalling pathways for one or both of these peptides, particularly given the low affinity of NPRA for BNP. We have investigated this hypothesis, using a genetically modified (knockout) mouse in which the gene encoding NPRA has been disrupted. Enzyme assays and NPRA-specific Western blots performed on tissues from wild-type mice demonstrate that ANP-activated cGMP synthesis provides a good index of NPRA protein expression, which ranges from maximal in adrenal gland, lung, kidney, and testis to minimal in heart and colon. In contrast, immunoreactive NPRA is not detectable in tissues isolated from NPRA knockout animals and ANP- and BNP-stimulatable GC activities are markedly reduced in all mutant tissues. However, testis and adrenal gland retain statistically significant, high-affinity responses to BNP. This residual response to BNP cannot be accounted for by natriuretic peptide receptor B, or any other known mammalian rGC, suggesting the presence of a novel receptor in these tissues that prefers BNP over ANP.

    View details for Web of Science ID 000170877900012

    View details for PubMedID 11513736

  • Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice JOURNAL OF CLINICAL INVESTIGATION Knowles, J. W., Esposito, G., Mao, L., Hagaman, J. R., Fox, J. E., Smithies, O., Rockman, H. A., Maeda, N. 2001; 107 (8): 975-984

    Abstract

    Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control.

    View details for Web of Science ID 000168152000009

    View details for PubMedID 11306601

  • Genetic modifiers of atherosclerosis in mice ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Knowles, J. W., Maeda, N. 2000; 20 (11): 2336-2345

    Abstract

    Atherosclerosis is a complex, multifactorial disease with both genetic and environmental determinants. Experimental investigation of the effects of these determinants on the development and progression of atherosclerosis has been greatly facilitated by the use of targeted mouse models of the disease, particularly those resulting from the absence of functional genes for apolipoprotein E or the low density lipoprotein receptor (LDLR). This review focuses on the influence on atherosclerosis of combining apoE or LDLR deficiencies with factors affecting atherogenesis, including (1) inflammatory processes, (2) glucose metabolism, (3) blood pressure, and (4) coagulation and fibrinolysis. We also discuss the general problem of using the mouse to test the effects on atherogenesis of human polymorphic variations and future ways of enhancing the usefulness of these mouse models.

    View details for Web of Science ID 000165306600002

    View details for PubMedID 11073835

  • Enhanced atherosclerosis and kidney dysfunction in eNOS(-)/(-)Apo(-)/(-) mice are ameliorated by enalapril treatment JOURNAL OF CLINICAL INVESTIGATION Knowles, J. W., Reddick, R. L., Jennette, J. C., Shesely, E. G., Smithies, O., Maeda, N. 2000; 105 (4): 451-458

    Abstract

    Hypertension and atherosclerosis are each important causes of morbidity and mortality in the developed world. We have investigated the interaction between these conditions by breeding mice that are atherosclerotic due to lack of apolipoprotein (apo) E with mice that are hypertensive due to lack of endothelial nitric oxide synthase (eNOS). The doubly deficient mice (nnee) have higher blood pressure (BP) and increased atherosclerotic lesion size but no change in plasma lipoprotein profiles compared with normotensive but atherosclerotic (NNee) mice. The nnee mice also develop kidney damage, evidenced by increased plasma creatinine, decreased kidney weight/body weight ratio, and glomerular lipid deposition and calcification. Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosis, and kidney dysfunction in nnee mice. In striking contrast, a genetic lack of inducible NOS, which does not affect BP, has no effect on the development of atherosclerotic lesions in Apoe(-/-) mice. We also observed a positive relationship between BP and size of atherosclerotic lesions These results suggest that the atherogenic effects of eNOS deficiency can be partially explained by an increase in BP and reemphasize the importance of controlling hypertension in preventing atherosclerosis.

    View details for Web of Science ID 000085446700008

    View details for PubMedID 10683374

  • Low salt intake down-regulates the guanylin signaling pathway in rat distal colon GASTROENTEROLOGY Li, Z. P., Knowles, J. W., Goyeau, D., Prabhakar, S., Short, D. B., Perkins, A. G., Goy, M. F. 1996; 111 (6): 1714-1721

    Abstract

    Guanylin, an endogenous gastrointestinal peptide, causes the translocation of NaCl from interstitial fluid to the intestinal lumen. The aim of this study was to examine whether changes in dietary salt intake lead to compensatory changes in expression of the guanylin signaling pathway.Rats received low-, normal-, or high-sodium diets for 1 week. Colonic guanylin expression was evaluated by Western and Northern blotting, rates of guanylin secretion by measuring biologically active guanylin released into the medium from colon explants, and expression of the guanylin receptor (C-type guanylate cyclase) by Northern blotting and bioassay.By every criterion, the low-salt diet reduced expression of guanylin to 30%-40% of the level found in control animals. Guanylin receptor expression was also decreased, although less dramatically and with a lower statistical significance. For both guanylin and guanylin receptor, the high-salt diet had no significant effect on expression.The data support the hypothesis that the guanylin pathway is down-regulated as an adaptive response to salt restriction.

    View details for Web of Science ID A1996VW29200039

    View details for PubMedID 8942754