Clinical Focus

  • Familial Hypercholesterolemia
  • Cardiomyopathy, Hypertrophic
  • Cardiovascular Disease
  • Insulin Resistance
  • Cardiology

Academic Appointments

Administrative Appointments

  • Chief Medical Officer, The FH Foundation (2012 - Present)

Honors & Awards

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

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 Hospital and Clinics (2010) CA
  • Residency:Stanford Hospital and Clinics (2005) CA
  • Medical Education:University of North Carolina - Chapel Hill (2003) NC
  • PhD, University of North Carolina, Chapel Hill, Genetics and Molecular Biology (2001)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2006)

Community and International Work

  • The FH Foundation


    Familial Hypercholesterolemia

    Partnering Organization(s)

    The FH Foundation



    Ongoing Project


    Opportunities for Student Involvement


  • Arbor Free Clinic


    Bay Area

    Ongoing Project


    Opportunities for Student Involvement


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

  • 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


Journal Articles

  • 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


    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


    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

  • 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


    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

  • 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


    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

  • 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


    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


    Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes but its causal role remains controversial. We used a Mendelian randomisation 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 cases and 64,731 controls). In conventional regression analyses a 1 SD decrease in adiponectin levels was correlated with a 0.31 SD (95%CIs: 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 of 1.75 (95%CIs: 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, 0.11, N=29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95%CIs: -0.38, -0.02; N=1,860) and no evidence of a relationship with type 2 diabetes (odds ratio 0.94; 95%CIs: 0.75, 1.19; N= 2,777 cases and 13,011 controls). 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%CIs: -0.07, 0.01; N=2,969) or type 2 diabetes (odds ratio per weighted adiponectin lowering allele: 0.99; 95%CIs: 0.95, 1.04; 15,960 cases vs. 64,731 controls). 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

  • 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
  • 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


    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

  • 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


    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

  • 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


    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


    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) ?mol/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): 134-9


    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 PubMedID 23750577

  • 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


    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 PubMedID 23726366

  • 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


    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

  • Exploring Predisposition and Treatment Response-the Promise of Genomics PROGRESS IN CARDIOVASCULAR DISEASES Pan, S., Knowles, J. W. 2012; 55 (1): 56-63


    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
  • 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


    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

  • 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-?


    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 Web of Science ID 000303106800023

    View details for PubMedID 22520528

  • 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)


    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 Web of Science ID 000295419100031

    View details for PubMedID 21935354

  • 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


    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?? 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

  • 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


    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

  • 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


    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 Web of Science ID 000283538000005

    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


    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??), 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


    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?

    View details for DOI 10.1038/nature09410

    View details for Web of Science ID 000282898700065

    View details for PubMedID 20881960

  • 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


    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

  • 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


    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

  • 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)


    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

  • 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


    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

  • 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


    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

  • 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


    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


    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

  • 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


    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


    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 Web of Science ID 000251396200008

    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


    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

  • 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

  • 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


    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


    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


    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


    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


    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


    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


    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


    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


    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

Conference Proceedings

  • OVERUSE OF LEFT VENTRICULOGRAPHY 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
  • Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans 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: 1266-1275


    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

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