Publications

The relationship between insulin resistance and ion mobility lipoprotein fractions. American journal of preventive cardiology Rowland, C. M., Abbasi, F., Shiffman, D., Knowles, J. W., McPhaul, M. J. 2023; 13: 100457 More

Abstract

Objective: Insulin resistance (IR) increases risk of type 2 diabetes and atherosclerotic cardiovascular disease and is associated with lipid and lipoprotein abnormalities including high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C). Lipoprotein size and lipoprotein subfractions (LS) have also been used to assist in identifying persons with IR. Associations of LS and IR have not been validated using both direct measures of IR and direct measures of LS. We assessed the usefulness of fasting lipoprotein subfractions (LS) by ion mobility to identify individuals with IR.Methods: Lipid panel, LS by ion mobility (LS-IM), and IR by steady-state plasma glucose (SSPG) concentration were assessed in 526 adult volunteers without diabetes. IR was defined as being in the highest tertile of SSPG concentration. LS-IM score was calculated by linear combination of regression coefficients from a stepwise regression analysis with SSPG concentration as the dependent variable. Improvement in prediction of IR was evaluated after combining LS-IM score with TG/HDL-C, TG/HDL-C and BMI as well as with TG/HDL-C, BMI, sex, race and ethnicity. IR prediction was evaluated by area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV) considering the highest 5% of scores as positive test.Results: Prediction of IR was similar by LS-IM score and TG/HDL-C (AUC=0.68; PPV=0.59 and AUC=0.70; PPV=0.59, respectively) and prediction was improved when LS-IM was combined with TG/HDL-C (AUC=0.73; PPV=0.70), TG/HDL-C and BMI (AUC=0.82; PPV=0.81) and with TG/HDL-C, BMI, sex, race and ethnicity (AUC=0.84; PPV=0.89).Conclusion: For identifying individuals with IR, LS-IM score and TG/HDL-C are comparable and their combination further improves IR prediction by TG/HDL-C alone. Among patients who have undergone IM testing, the LS-IM score may assist prioritization of subjects for further evaluation and interventions to reduce IR.

View details for DOI 10.1016/j.ajpc.2022.100457

View details for PubMedID 36619297

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis. Nature communications Bielczyk-Maczynska, E., Zhao, M., Zushin, P. H., Schnurr, T. M., Kim, H. J., Li, J., Nallagatla, P., Sangwung, P., Park, C. Y., Cornn, C., Stahl, A., Svensson, K. J., Knowles, J. W. 2022; 13 (1): 7408 More

Abstract

Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.

View details for DOI 10.1038/s41467-022-35069-9

View details for PubMedID 36456565

View details for PubMedCentralID 508922

Chronic liver disease-related mortality in diabetes before and during the COVID-19 in the United States. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver Kim, D., Alshuwaykh, O., Dennis, B. B., Cholankeril, G., Knowles, J. W., Ahmed, A. 2022 More

Abstract

BACKGROUND: Global pandemic of COVID-19 represents an unprecedented challenge. COVID-19 has predominantly targeted vulnerable populations with pre-existing chronic medical diseases, such as diabetes and chronic liver disease.AIMS: We estimated chronic liver disease-related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.METHODS: Utilizing the US national mortality database and Census, we determined the quarterly age-standardized chronic liver disease-related mortality and quarterly percentage change (QPC) among individuals with diabetes.RESULTS: The quarterly age-standardized mortality for chronic liver disease and/or cirrhosis among individuals with diabetes remained stable before the COVID-19 pandemic and sharply increased during the COIVD-19 pandemic at a QPC of 8.5%. The quarterly mortality from nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) increased markedly during the COVID-19 pandemic. Mortality for hepatitis C virus (HCV) infection declined with a quarterly rate of -3.3% before the COVID-19 pandemic and remained stable during the COVID-19 pandemic. While ALD- and HCV-related mortality was higher in men than in women, NAFLD-related mortality in women was higher than in men.CONCLUSIONS: The sharp increase in mortality for chronic liver disease and/or cirrhosis among individuals with diabetes during the COVID-19 pandemic was associated with increased mortality from NAFLD and ALD.

View details for DOI 10.1016/j.dld.2022.09.006

View details for PubMedID 36182570

Analysis of Insulin Resistance Among Children and Adolescents in Slovenia With Hypercholesterolemia After Treatment With Statins. JAMA network open Groselj, U., Sikonja, J., Mlinaric, M., Kotnik, P., Battelino, T., Knowles, J. W. 2022; 5 (9): e2231097 More

View details for DOI 10.1001/jamanetworkopen.2022.31097

View details for PubMedID 36094507

STATIN THERAPY IS NOT ASSOCIATED WITH INSULIN RESISTANCE IN CHILDREN AND ADOLESCENTS WITH FAMILIAL HYPERCHOLESTEROLAEMIA Groselj, U., Sikonja, J., Mlinaric, M., Kotnik, P., Battelino, T., Knowles, J. W. ELSEVIER IRELAND LTD. 2022: E173 More

View details for Web of Science ID 000853696400488

Creation of the American Heart Association Journals' Equity, Diversity, and Inclusion Editorial Board: The Next Step to Achieving the 2024 Impact Goal. Circulation Lewis, E. F., Beaty, C., Boltze, J., Breathett, K., Clair, W. K., de Las Fuentes, L., Essien, U. R., Goodell, H., Hinson, H. E., Kershaw, K. N., Knowles, J. W., Mazimba, S., Mujahid, M., Okafor, H. E., Woo Park, K., Schultz, J. 2022: 101161CIRCULATIONAHA122061450 More

View details for DOI 10.1161/CIRCULATIONAHA.122.061450

View details for PubMedID 35862071

Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab. Circulation Hagström, E., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Danchin, N., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Liberopoulos, E., Marx, N., McGinniss, J., Manvelian, G., Pordy, R., Scemama, M., White, H. D., Zeiher, A. M., Schwartz, G. G. 2022: 101161CIRCULATIONAHA121057807 More

Abstract

Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain.The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACEs; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACEs were assessed in adjusted Cox proportional hazards and propensity score-matched models.Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; Ptrend<0.0001) and after adjustment for low-density lipoprotein cholesterol (Ptrend=0.035). Higher baseline apoB stratum was associated with greater relative (Ptrend<0.0001) and absolute reduction in MACEs with alirocumab versus placebo. In the alirocumab group, the incidence of MACEs after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACEs after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa.In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACEs increased across baseline apoB strata. Alirocumab reduced MACEs across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACEs, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of an apoB level ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome.URL: https://www.gov. Unique identifier: NCT01663402.

View details for DOI 10.1161/CIRCULATIONAHA.121.057807

View details for PubMedID 35770629

Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants. Stem cell research Manhas, A., Jahng, J. W., Vera, C. D., Shenoy, S. P., Knowles, J. W., Wu, J. C. 2022; 61: 102774 More

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterized by a thick left ventricular wall and an increased risk of arrhythmias, heart failure, and sudden cardiac death. The MYBPC3 and PRAKG2 are known causal genes for HCM. Here we generated two human-induced pluripotent stem cell lines from two HCM patients carrying two heterozygous mutations in MYBPC3 (c.459delC) and PRKAG2 (c.1703C > T). Both iPSC lines expressed pluripotent markers, had a normal karyotype, and were able to differentiate into three germ layers, making them potentially valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to these two variants.

View details for DOI 10.1016/j.scr.2022.102774

View details for PubMedID 35413566

Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes. Genome medicine Gloudemans, M. J., Balliu, B., Nachun, D., Schnurr, T. M., Durrant, M. G., Ingelsson, E., Wabitsch, M., Quertermous, T., Montgomery, S. B., Knowles, J. W., Carcamo-Orive, I. 2022; 14 (1): 31 More

Abstract

BACKGROUND: Identification of causal genes for polygenic human diseases has been extremely challenging, and our understanding of how physiological and pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature of cardiometabolic disease, including type 2 diabetes, obesity, and dyslipidemia, lacks well-powered genome-wide association studies (GWAS), and therefore, few associated loci and causal genes have been identified.METHODS: Here, we perform and integrate linkage disequilibrium (LD)-adjusted colocalization analyses across nine cardiometabolic traits (fasting insulin, fasting glucose, insulin sensitivity, insulin sensitivity index, type 2 diabetes, triglycerides, high-density lipoprotein, body mass index, and waist-hip ratio) combined with expression and splicing quantitative trait loci (eQTLs and sQTLs) from five metabolically relevant human tissues (subcutaneous and visceral adipose, skeletal muscle, liver, and pancreas). To elucidate the upstream regulators and functional mechanisms for these genes, we integrate their transcriptional responses to 21 relevant physiological and pharmacological perturbations in human adipocytes, hepatocytes, and skeletal muscle cells and map their protein-protein interactions.RESULTS: We identify 470 colocalized loci and prioritize 207 loci with a single colocalized gene. Patterns of shared colocalizations across traits and tissues highlight different potential roles for colocalized genes in cardiometabolic disease and distinguish several genes involved in pancreatic beta-cell function from others with a more direct role in skeletal muscle, liver, and adipose tissues. At the loci with a single colocalized gene, 42 of these genes were regulated by insulin and 35 by glucose in perturbation experiments, including 17 regulated by both. Other metabolic perturbations regulated the expression of 30 more genes not regulated by glucose or insulin, pointing to other potential upstream regulators of candidate causal genes.CONCLUSIONS: Our use of transcriptional responses under metabolic perturbations to contextualize genetic associations from our custom colocalization approach provides a list of likely causal genes and their upstream regulators in the context of IR-associated cardiometabolic risk.

View details for DOI 10.1186/s13073-022-01036-8

View details for PubMedID 35292083

Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes Gloudemans, M. J., Balliu, B., Nachun, D., Durrant, M. G., Ingelsson, E., Wabitsch, M., Quertermous, T., Montgomery, S. B., Knowles, J., Carcamo-Orive, I. W B SAUNDERS CO-ELSEVIER INC. 2022: S24-S25 More

View details for DOI 10.1016/j.metabol.2021.155025

View details for Web of Science ID 000778891500062

A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome medicine Marwaha, S., Knowles, J. W., Ashley, E. A. 2022; 14 (1): 23 More

Abstract

Rare diseases affect 30 million people in the USA and more than 300-400 million worldwide, often causing chronic illness, disability, and premature death. Traditional diagnostic techniques rely heavily on heuristic approaches, coupling clinical experience from prior rare disease presentations with the medical literature. A large number of rare disease patients remain undiagnosed for years and many even die without an accurate diagnosis. In recent years, gene panels, microarrays, and exome sequencing have helped to identify the molecular cause of such rare and undiagnosed diseases. These technologies have allowed diagnoses for a sizable proportion (25-35%) of undiagnosed patients, often with actionable findings. However, a large proportion of these patients remain undiagnosed. In this review, we focus on technologies that can be adopted if exome sequencing is unrevealing. We discuss the benefits of sequencing the whole genome and the additional benefit that may be offered by long-read technology, pan-genome reference, transcriptomics, metabolomics, proteomics, and methyl profiling. We highlight computational methods to help identify regionally distant patients with similar phenotypes or similar genetic mutations. Finally, we describe approaches to automate and accelerate genomic analysis. The strategies discussed here are intended to serve as a guide for clinicians and researchers in the next steps when encountering patients with non-diagnostic exomes.

View details for DOI 10.1186/s13073-022-01026-w

View details for PubMedID 35220969

Online Patient Education Materials Related to Lipoprotein(a): Readability Assessment. Journal of medical Internet research Pearson, K., Ngo, S., Ekpo, E., Sarraju, A., Baird, G., Knowles, J., Rodriguez, F. 1800; 24 (1): e31284 More

Abstract

BACKGROUND: Lipoprotein(a) (Lp(a)) is a highly proatherogenic lipid fraction that is a clinically significant risk modifier. Patients wanting to learn more about Lp(a) are likely to use online patient educational materials (OPEMs). However, the readability of OPEMs may exceed the health literacy of the public.OBJECTIVE: This study aims to assess the readability of OPEMs related to Lp(a). We hypothesized that the readability of these online materials would exceed the sixth grade level recommended by the American Medical Association.METHODS: Using an online search engine, we queried the top 20 search results from 10 commonly used Lp(a)-related search terms to identify a total of 200 websites. We excluded duplicate websites, advertised results, research journal articles, or non-patient-directed materials, such as those intended only for health professionals or researchers. Grade level readability was calculated using 5 standard readability metrics (automated readability index, SMOG index, Coleman-Liau index, Gunning Fog score, Flesch-Kincaid score) to produce robust point (mean) and interval (CI) estimates of readability. Generalized estimating equations were used to model grade level readability by each search term, with the 5 readability scores nested within each OPEM.RESULTS: A total of 27 unique websites were identified for analysis. The average readability score for the aggregated results was a 12.2 (95% CI 10.9798-13.3978) grade level. OPEMs were grouped into 6 categories by primary source: industry, lay press, research foundation and nonprofit organizations, university or government, clinic, and other. The most readable category was OPEMs published by universities or government agencies (9.0, 95% CI 6.8-11.3). The least readable OPEMs on average were the ones published by the lay press (13.0, 95% CI 11.2-14.8). All categories exceeded the sixth grade reading level recommended by the American Medical Association.CONCLUSIONS: Lack of access to readable OPEMs may disproportionately affect patients with low health literacy. Ensuring that online content is understandable by broad audiences is a necessary component of increasing the impact of novel therapeutics and recommendations regarding Lp(a).

View details for DOI 10.2196/31284

View details for PubMedID 35014955

Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting. The New England journal of medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Baid, G., Bernstein, J. A., Ceresnak, S., Chang, P. C., Christle, J. W., Chubb, H., Dalton, K. P., Dunn, K., Garalde, D. R., Guillory, J., Knowles, J. W., Kolesnikov, A., Ma, M., Moscarello, T., Nattestad, M., Perez, M., Ruzhnikov, M. R., Samadi, M., Setia, A., Wright, C., Wusthoff, C. J., Xiong, K., Zhu, T., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022 More

View details for DOI 10.1056/NEJMc2112090

View details for PubMedID 35020984

Interactions of physical activity, muscular fitness, adiposity, and genetic risk for NAFLD. Hepatology communications Schnurr, T. M., Katz, S. F., Justesen, J. M., O'Sullivan, J. W., Saliba-Gustafsson, P., Assimes, T. L., Carcamo-Orive, I., Ahmed, A., Ashley, E. A., Hansen, T., Knowles, J. W. 2022 More

Abstract

Genetic predisposition and unhealthy lifestyle are risk factors for nonalcoholic fatty liver disease (NAFLD). We investigated whether the genetic risk of NAFLD is modified by physical activity, muscular fitness, and/or adiposity. In up to 242,524 UK Biobank participants without excessive alcohol intake or known liver disease, we examined cross-sectional interactions and joint associations of physical activity, muscular fitness, body mass index (BMI), and a genetic risk score (GRS) with alanine aminotransferase (ALT) levels and the proxy definition for suspected NAFLD of ALT levels > 30 U/L in women and >40 U/L in men. Genetic predisposition to NAFLD was quantified using a GRS consisting of 68 loci known to be associated with chronically elevated ALT. Physical activity was assessed using accelerometry, and muscular fitness was estimated by measuring handgrip strength. We found that increased physical activity and grip strength modestly attenuate genetic predisposition to elevation in ALT levels, whereas higher BMI markedly amplifies it (all p values < 0.001). Among those with normal weight and high level of physical activity, the odds of suspected NAFLD were 1.6-fold higher in those with high versus low genetic risk (reference group). In those with high genetic risk, the odds of suspected NAFLD were 12-fold higher in obese participants with low physical activity versus those with normal weight and high physical activity (odds ratio for NAFLD = 19.2 and 1.6, respectively, vs. reference group). Conclusion: In individuals with high genetic predisposition for NAFLD, maintaining a normal body weight and increased physical activity may reduce the risk of NAFLD.

View details for DOI 10.1002/hep4.1932

View details for PubMedID 35293152

Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Clinically Observed Longitudinal Cholesterol Exposure. Circulation. Genomic and precision medicine Clarke, S. L., Tcheandjieu, C., Hilliard, A. T., Lee, M., Lynch, J., Chang, K. M., Miller, D., Knowles, J. W., O'Donnell, C., Tsao, P., Rader, D. J., Wilson, P. W., Sun, Y. V., Gaziano, M., Assimes, T. L. 2022: CIRCGEN121003501 More

Abstract

Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered.We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants in LDLR, APOB, and PCSK9 were assessed by custom genotype array.In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24-1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08-1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available.The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.

View details for DOI 10.1161/CIRCGEN.121.003501

View details for PubMedID 35143253

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis Nature Communications Bielczyk-Maczynska, E., Zhao, M., Zushin, P. H., Schnurr, T. M., Kim, H., Li, J., Sangwung, P., Nallagatla, P., Park, C., Cornn, C., Stahl, A., Svensson, K. J., Knowles, J. W. 2022 More

View details for DOI 10.1038/s41467-022-35069-9

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genetics in medicine : official journal of the American College of Medical Genetics Chora, J. R., Iacocca, M. A., Tichy, L., Wand, H., Kurtz, C. L., Zimmermann, H., Leon, A., Williams, M., Humphries, S. E., Hooper, A. J., Trinder, M., Brunham, L. R., Costa Pereira, A., Jannes, C. E., Chen, M., Chonis, J., Wang, J., Kim, S., Johnston, T., Soucek, P., Kramarek, M., Leigh, S. E., Carrie, A., Sijbrands, E. J., Hegele, R. A., Freiberger, T., Knowles, J. W., Bourbon, M., ClinGen Familial Hypercholesterolemia Expert Panel 1800 More

Abstract

PURPOSE: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.METHODS: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached.RESULTS: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others.CONCLUSION: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.

View details for DOI 10.1016/j.gim.2021.09.012

View details for PubMedID 34906454

Signaling defects associated with insulin resistance in non-diabetic and diabetic individuals and modification by sex. The Journal of clinical investigation Haider, N., Lebastchi, J., Jayavelu, A. K., Batista, T. M., Pan, H., Dreyfuss, J. M., Carcamo-Orive, I., Knowles, J. W., Mann, M., Kahn, C. R. 2021 More

Abstract

Insulin resistance is present in one-quarter of the general population, predisposing to a wide-range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using IPS cell-derived myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type-2-diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR and TBC1D1, in addition to changes in protein phosphorylation involved in Rho/Rac signaling, chromatin organization and RNA processing. There were also striking differences in the phosphoproteome in cells from males versus females. These sex-specific and insulin resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences in males and females, many of which are shared with diabetes, and contribute to differences in physiology and disease.

View details for DOI 10.1172/JCI151818

View details for PubMedID 34506305

Statins Are Associated With Increased Insulin Resistance and Secretion. Arteriosclerosis, thrombosis, and vascular biology Abbasi, F., Lamendola, C., Harris, C. S., Harris, V., Tsai, M., Tripathi, P., Abbas, F., Reaven, G., Reaven, P., Snyder, M. P., Kim, S. H., Knowles, J. W. 2021: ATVBAHA121316159 More

Abstract

OBJECTIVE: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01).CONCLUSIONS: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02437084.

View details for DOI 10.1161/ATVBAHA.121.316159

View details for PubMedID 34433298

Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar. Journal of the American College of Cardiology Kim, D. S., Gloyn, A. L., Knowles, J. W. 2021; 78 (5): 496-512 More

Abstract

Type 2 diabetes (T2D) is highly prevalent and is a strong contributor for cardiovascular disease. However, there is significant heterogeneity in disease pathogenesis and the risk of complications. Enormous progress has been made in our ability to catalog genetic variation associated with T2D risk and variation in disease-relevant quantitative traits. These discoveries hold the potential to shed light on tractable targets and pathways for safe and effective therapeutic development, but the promise of precision medicine has been slow to be realized. Recent studies have identified subgroups of individuals with differential risk for intermediate phenotypes (eg, lipid levels, fasting insulin, body mass index) that contribute to T2D risk, helping to account for the observed clinical heterogeneity. These "partitioned genetic risk scores" not only have the potential to identify patients at greatest risk of cardiovascular disease and rapid disease progression, but also could aid patient stratification bridging the gap toward precision medicine for T2D.

View details for DOI 10.1016/j.jacc.2021.03.346

View details for PubMedID 34325839

Diverse Racial/Ethnic Group Underreporting and Underrepresentation in High-Impact Cholesterol Treatment Trials. Circulation Sarraju, A., Valencia, A., Knowles, J. W., Maron, D. J., Rodriguez, F. 2021; 143 (24): 2409-2411 More

View details for DOI 10.1161/CIRCULATIONAHA.120.050034

View details for PubMedID 34125567

Health disparities in cardiometabolic risk among Black and Hispanic youth in the United States. American journal of preventive cardiology Katz, S. F., Rodriguez, F., Knowles, J. W. 2021; 6: 100175 More

Abstract

Cardiometabolic risk factors in children and adolescents track into adulthood and are associated with increased risk of atherosclerotic cardiovascular disease. The purpose of this review is to examine the pervasive race and ethnic disparities in cardiometabolic risk factors among Black and Hispanic youth in the United States. We focus on three traditional cardiometabolic risk factors (obesity, type 2 diabetes mellitus, and dyslipidemia) as well as on the emerging cardiometabolic risk factor of non-alcoholic fatty liver disease. Additionally, we highlight interventions aimed at improving cardiometabolic health among these minority pediatric populations. Finally, we advocate for continued research on effective prevention strategies to reduce cardiometabolic risk and avert further disparities in cardiovascular morbidity and mortality.

View details for DOI 10.1016/j.ajpc.2021.100175

View details for PubMedID 34327498

Generation of two heterozygous MYBPC3 mutation-carrying human iPSC lines, SCVIi001-A and SCVIi002-A, for modeling hypertrophic cardiomyopathy. Stem cell research Liu, L., Shenoy, S. P., Jahng, J. W., Liu, Y., Knowles, J. W., Zhuge, Y., Wu, J. C. 2021; 53: 102279 More

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that can cause sudden cardiac death and heart failure. HCM often arises from mutations in sarcomeric genes, among which the MYBPC3 is the most frequently mutated. Here we generated two human induced pluripotent stem cell (iPSC) lines from a HCM patient who has a familial history of HCM and his daughter who carries the pathogenic non-coding mutation. All lines show the typical morphology of pluripotent cells, a high expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers. These lines provide a valuable resource for studying the molecular basis of HCM and drug screening for HCM.

View details for DOI 10.1016/j.scr.2021.102279

View details for PubMedID 33743363

Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics. Nature genetics Bonder, M. J., Smail, C., Gloudemans, M. J., Fresard, L., Jakubosky, D., D'Antonio, M., Li, X., Ferraro, N. M., Carcamo-Orive, I., Mirauta, B., Seaton, D. D., Cai, N., Vakili, D., Horta, D., Zhao, C., Zastrow, D. B., Bonner, D. E., HipSci Consortium, iPSCORE consortium, Undiagnosed Diseases Network, PhLiPS consortium, Wheeler, M. T., Kilpinen, H., Knowles, J. W., Smith, E. N., Frazer, K. A., Montgomery, S. B., Stegle, O., Jan Bonder, M., Seaton, D., Jakubosky, D. A., Brown, C. D., Park, Y. 2021 More

Abstract

Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.

View details for DOI 10.1038/s41588-021-00800-7

View details for PubMedID 33664507

Validation of an Integrated Risk Tool, Including Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in Multiple Ethnicities and Ancestries. The American journal of cardiology Weale, M. E., Riveros-Mckay, F., Selzam, S., Seth, P., Moore, R., Tarran, W. A., Gradovich, E., Giner-Delgado, C., Palmer, D., Wells, D., Saffari, A., Sivley, R. M., Lachapelle, A. S., Wand, H., Clarke, S. L., Knowles, J. W., O'Sullivan, J. W., Ashley, E. A., McVean, G., Plagnol, V., Donnelly, P. 2021 More

Abstract

The American College of Cardiology / American Heart Association pooled cohort equations tool (ASCVD-PCE) is currently recommended to assess 10-year risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD-PCE does not currently include genetic risk factors. Polygenic risk scores (PRSs) have been shown to offer a powerful new approach to measuring genetic risk for common diseases, including ASCVD, and to enhance risk prediction when combined with ASCVD-PCE. Most work to date, including the assessment of tools, has focused on performance in individuals of European ancestries. Here we present evidence for the clinical validation of a new integrated risk tool (IRT), ASCVD-IRT, which combines ASCVD-PCE with PRS to predict 10-year risk of ASCVD across diverse ethnicity and ancestry groups. We demonstrate improved predictive performance of ASCVD-IRT over ASCVD-PCE, not only in individuals of self-reported White ethnicities (net reclassification improvement (NRI) (with 95% confidence interval) = 2.7% (1.1 - 4.2)) but also Black / African American / Black Caribbean / Black African (NRI = 2.5% (0.6 - 4.3)) and South Asian (Indian, Bangladeshi or Pakistani) ethnicities (NRI = 8.7% (3.1 - 14.4)). NRI confidence intervals were wider and included zero for ethnicities with smaller sample sizes, including Hispanic (NRI = 7.5% (-1.4 - 16.5)), but PRS effect sizes in these ethnicities were significant and of comparable size to those seen in individuals of White ethnicities. Comparable results were obtained when individuals were analysed by genetically inferred ancestry. Together, these results validate the performance of ASCVD-IRT in multiple ethnicities and ancestries, and favour their generalisation to all ethnicities and ancestries.

View details for DOI 10.1016/j.amjcard.2021.02.032

View details for PubMedID 33675770

RECOMMENDATIONS FOR LDLR VARIANT INTERPRETATION BY THE CLINGEN'S FAMILIAL HYPERCHOLESTEROLEMIA EXPERT PANEL Chora, J., Iacocca, M., Tichy, L., Wand, H., Kurtz, L. C., Zimmermann, H., Meredith, A., Williams, M., Humphries, S. E., Hooper, A. J., Brunham, L., Pereira, A., Chen, M., Wang, J., Trinder, M., Jannes, C., Chonis, J., Kim, S., Pesaran, T., Johnston, T., Carrie, A., Leigh, S., Hegele, R. A., Sijbrands, E., Freiberger, T., Knowles, J. W., Bourbon, M. LIPPINCOTT WILLIAMS & WILKINS. 2021 More

View details for Web of Science ID 000612833500180

The need for polygenic score reporting standards in evidence-based practice: lipid genetics use case. Current opinion in lipidology Wand, H. n., Knowles, J. W., Clarke, S. L. 2021 More

Abstract

Polygenic scores (PGS) are used to quantify the genetic predisposition for heritable traits, with hypothesized utility for personalized risk assessments. Lipid PGS are primed for clinical translation, but evidence-based practice changes will require rigorous PGS standards to ensure reproducibility and generalizability. Here we review applicable reporting and technical standards for dyslipidemia PGS translation along phases of the ACCE (Analytical validity, Clinical validity, Clinical utility, Ethical considerations) framework for evaluating genetic tests.New guidance suggests existing standards for study designs incorporating the ACCE framework are applicable to PGS and should be adopted. One recent example is the Clinical Genomics Resource (ClinGen) and Polygenic Score Catalog's PRS reporting standards, which define minimal requirements for describing rationale for score development, study population definitions and data parameters, risk model development and application, risk model evaluation, and translational considerations, such as generalizability beyond the target population studied.Lipid PGS are likely to be integrated into clinical practice in the future. Clinicians will need to be prepared to determine if and when lipid PGS is useful and valid. This decision-making will depend on the quality of evidence for the clinical use of PGS. Establishing reporting standards for PGS will help facilitate data sharing and transparency for critical evaluation, ultimately benefiting the efficiency of evidence-based practice.

View details for DOI 10.1097/MOL.0000000000000733

View details for PubMedID 33538426

An integrated approach to identify environmental modulators of genetic risk factors for complex traits. American journal of human genetics Balliu, B., Carcamo-Orive, I., Gloudemans, M. J., Nachun, D. C., Durrant, M. G., Gazal, S., Park, C. Y., Knowles, D. A., Wabitsch, M., Quertermous, T., Knowles, J. W., Montgomery, S. B. 2021 More

Abstract

Complex traits and diseases can be influenced by both genetics and environment. However, given the large number of environmental stimuli and power challenges for gene-by-environment testing, it remains a critical challenge to identify and prioritize specific disease-relevant environmental exposures. We propose a framework for leveraging signals from transcriptional responses to environmental perturbations to identify disease-relevant perturbations that can modulate genetic risk for complex traits and inform the functions of genetic variants associated with complex traits. We perturbed human skeletal-muscle-, fat-, and liver-relevant cell lines with 21 perturbations affecting insulin resistance, glucose homeostasis, and metabolic regulation in humans and identified thousands of environmentally responsive genes. By combining these data with GWASs from 31 distinct polygenic traits, we show that the heritability of multiple traits is enriched in regions surrounding genes responsive to specific perturbations and, further, that environmentally responsive genes are enriched for associations with specific diseases and phenotypes from the GWAS Catalog. Overall, we demonstrate the advantages of large-scale characterization of transcriptional changes in diversely stimulated and pathologically relevant cells to identify disease-relevant perturbations.

View details for DOI 10.1016/j.ajhg.2021.08.014

View details for PubMedID 34582792

Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Cell metabolism Jiang, Z., Zhao, M., Voilquin, L., Jung, Y., Aikio, M. A., Sahai, T., Dou, F. Y., Roche, A. M., Carcamo-Orive, I., Knowles, J. W., Wabitsch, M., Appel, E. A., Maikawa, C. L., Camporez, J. P., Shulman, G. I., Tsai, L., Rosen, E. D., Gardner, C. D., Spiegelman, B. M., Svensson, K. J. 2021 More

Abstract

With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease.

View details for DOI 10.1016/j.cmet.2021.07.010

View details for PubMedID 34348115

Predictive network modeling in human induced pluripotent stem cells identifies key driver genes for insulin responsiveness. PLoS computational biology Carcamo-Orive, I., Henrion, M. Y., Zhu, K., Beckmann, N. D., Cundiff, P., Moein, S., Zhang, Z., Alamprese, M., D'Souza, S. L., Wabitsch, M., Schadt, E. E., Quertermous, T., Knowles, J. W., Chang, R. 2020; 16 (12): e1008491 More

Abstract

Insulin resistance (IR) precedes the development of type 2 diabetes (T2D) and increases cardiovascular disease risk. Although genome wide association studies (GWAS) have uncovered new loci associated with T2D, their contribution to explain the mechanisms leading to decreased insulin sensitivity has been very limited. Thus, new approaches are necessary to explore the genetic architecture of insulin resistance. To that end, we generated an iPSC library across the spectrum of insulin sensitivity in humans. RNA-seq based analysis of 310 induced pluripotent stem cell (iPSC) clones derived from 100 individuals allowed us to identify differentially expressed genes between insulin resistant and sensitive iPSC lines. Analysis of the co-expression architecture uncovered several insulin sensitivity-relevant gene sub-networks, and predictive network modeling identified a set of key driver genes that regulate these co-expression modules. Functional validation in human adipocytes and skeletal muscle cells (SKMCs) confirmed the relevance of the key driver candidate genes for insulin responsiveness.

View details for DOI 10.1371/journal.pcbi.1008491

View details for PubMedID 33362275

SPECIFICATION OF ACMG/AMP GUIDELINES FOR STANDARDIZED VARIANT INTERPRETATION IN FAMILIAL HYPERCHOLESTEROLEMIA: ON BEHALF OF THE CLINGEN FH VARIANT CURATION EXPERT PANEL Iacocca, M. A., Chora, J. R., Freiberger, T., Carrie, A., Sijbrands, E. J., Wand, H., Williams, M., Zimmermann, H., Leon, A., Kurtz, C. L., Tichy, L., Alves, A. C., Wang, J., Cuchel, M., Humphries, S. E., Defesche, J. C., Mata, P., Santos, R. D., Kullo, I. J., Brunham, L. R., Hegele, R. A., Knowles, J. W., Bourbon, M. ELSEVIER IRELAND LTD. 2020: E5 More

View details for Web of Science ID 000748958900013

RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia Watts, G. F., Schwabe, C., Scott, R., Gladding, P., Sullivan, D., Baker, J., Clifton, P., Hamilton, J., Given, B., San Martin, J., Melquist, S., Knowles, J. W., Goldberg, Hegele, R., Ballantyne, C. OXFORD UNIV PRESS. 2020: 3331 More

View details for Web of Science ID 000606106303338

RNA interference targeting apolipoprotein C-III with ARO-APOC3 in healthy volunteers mimics lipid and lipoprotein findings seen in subjects with inherited apolipoprotein C-III deficiency Schwabe, C., Scott, R., Sullivan, D., Baker, J., Clifton, P., Hamilton, J., Given, B., San Martin, J., Melquist, S., Watts, G. F., Goldberg, Knowles, J. W., Hegele, R., Ballantyne, C. OXFORD UNIV PRESS. 2020: 3330 More

View details for Web of Science ID 000606106303337

Children with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE FH Registry. The Journal of pediatrics de Ferranti, S. D., Shrader, P., Linton, M. F., Knowles, J. W., Hudgins, L. C., Benuck, I., Kindt, I., O'Brien, E. C., Peterson, A. L., Ahmad, Z. S., Clauss, S., Duell, P. B., Shapiro, M. D., Wilemon, K., Gidding, S. S., Neal, W. 2020 More

Abstract

OBJECTIVE: To describe enrollment characteristics of youth in the CAscade SCreening for Awareness and DEtection (CASCADE) Familial Hypercholesterolemia Registry.STUDY DESIGN: Cross-sectional analysis of 493 participants <18 years old with heterozygous FH recruited from US lipid clinics (n=20), between April 1, 2014 and January 12, 2018. At enrollment, some were new patients and some were in care. Clinical characteristics are described, including lipid levels and lipid lowering treatments (LLTs).RESULTS: Mean age at diagnosis was 9.4 (4.0) years; 47% female, 68% white and 12% Hispanic. Average (SD) highest LDL-C was 238 (61) mg/dL prior to treatment. Lipid lowering therapy (LLT) was used by 64% of participants; 56% were treated with statin. LDL-C declined 84 mg/dL (33%) among those treated with LLT; statins produced the greatest decline, 100 mg/dL (39% reduction). At enrollment, 39% had reached an LDL-C goal, either <130 mg/dL or ≥50% decrease from pre-treatment; 20% of those on LLT reached both goals.CONCLUSIONS: Among youth enrolled in CASCADE FH, diagnosis occurred relatively late, only 77% of children eligible for LLT were on treatment and 39% of those treated met LDL-C goals. Opportunities exist for earlier diagnosis, broader use of LLT, and greater LDL-C lowering.

View details for DOI 10.1016/j.jpeds.2020.09.042

View details for PubMedID 32976895

Expression of Glycolytic Enzymes in Induced Pluripotent Stem Cells, Derived Megakaryocytes, and Endothelial Cells Chandra, A., Vaidya, D., Chang, R., Knowles, J., Carcamo-Oribe, I., Kammers, K., Martin, J., Taub, M., Hoyle, D., Gao, Y., Yanek, L., Kral, B., Faraday, N., Becker, D., Mathias, R., Cheng, L., Leek, J., Wang, Z., Becker, L. LIPPINCOTT WILLIAMS & WILKINS. 2020 More

View details for DOI 10.1161/res.127.suppl_1.330

View details for Web of Science ID 000606541500099

Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats. Nature communications Jakubosky, D., Smith, E. N., D'Antonio, M., Jan Bonder, M., Young Greenwald, W. W., D'Antonio-Chronowska, A., Matsui, H., i2QTL Consortium, Stegle, O., Montgomery, S. B., DeBoever, C., Frazer, K. A., Bonder, M. J., Cai, N., Carcamo-Orive, I., D'Antonio, M., Frazer, K. A., Young Greenwald, W. W., Jakubosky, D., Knowles, J. W., Matsui, H., McCarthy, D. J., Mirauta, B. A., Montgomery, S. B., Quertermous, T., Seaton, D. D., Smail, C., Smith, E. N., Stegle, O. 2020; 11 (1): 2928 More

Abstract

Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assemble a set of 719 deep whole genome sequencing (WGS) samples (mean 42*) from 477 distinct individuals which we use to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We use 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and develop a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date.

View details for DOI 10.1038/s41467-020-16481-5

View details for PubMedID 32522985

Properties of structural variants and short tandem repeats associated with gene expression and complex traits. Nature communications Jakubosky, D., D'Antonio, M., Bonder, M. J., Smail, C., Donovan, M. K., Young Greenwald, W. W., Matsui, H., i2QTL Consortium, D'Antonio-Chronowska, A., Stegle, O., Smith, E. N., Montgomery, S. B., DeBoever, C., Frazer, K. A., Bonder, M. J., Cai, N., Carcamo-Orive, I., D'Antonio, M., Frazer, K. A., Young Greenwald, W. W., Jakubosky, D., Knowles, J. W., Matsui, H., McCarthy, D. J., Mirauta, B. A., Montgomery, S. B., Quertermous, T., Seaton, D. D., Smail, C., Smith, E. N., Stegle, O. 2020; 11 (1): 2927 More

Abstract

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits.

View details for DOI 10.1038/s41467-020-16482-4

View details for PubMedID 32522982

Insulin Resistance and Mitochondrial Dysfunction Mediated by Nat1 Deficiency Sangwung, P., Fathzadeh, M., Knowles, J. AMER DIABETES ASSOC. 2020 More

View details for DOI 10.2337/db20-1736-P

View details for Web of Science ID 000554509804004

Gaps in Dyslipidemia Care Among Working-Aged Individuals With Employer-Sponsored Health Care. Journal of the American Heart Association Shiffman, D., Louie, J. Z., Devlin, J. J., Knowles, J. W., McPhaul, M. J. 2020: e015807 More

Abstract

Background The American Heart Association and American College of Cardiology guidelines defined patient-management groups that would benefit from lowering of low-density lipoprotein cholesterol (LDL-C). We assessed gaps in dyslipidemia care among employees and spouses with health benefits. Methods and Results We studied 17889 employees and spouses who were covered by an employer-sponsored health plan and participated in an annual health assessment. Using medical claims, laboratory tests, and risk assessment questionnaires, we found that 43% of participants were in one of 4 patient-management groups: secondary prevention, severe hypercholesterolemia (LDL-C ≥190mg/dL at least once in the preceding 5years), diabetes mellitus, or elevated 10-year risk of cardiovascular disease. To assess gaps in dyslipidemia care, we used LDL-C ≤70mg/dL as the goal for both the secondary prevention group and those in the elevated 10-year risk group with >20% risk; LDL-C ≤100mg/dL was used for the other groups. Among those in patient-management groups, 27.3% were in the secondary prevention group, 7.4% were in the severe hypercholesterolemia group, 29.9% were in the diabetes mellitus group, and 35.4% were in the elevated 10-year risk group. About 74% of those in patient-management groups had above-goal LDL-C levels, whereas only 31% had evidence of a lipid-lowering therapy in the past 6months: 45% in the secondary prevention group, 31% in the severe hypercholesterolemia group, 36% in the diabetes mellitus group, and 17% in the elevated 10-year risk group. Conclusions The substantial gaps in LDL-C treatment and goal attainment among members of an employer-sponsored medical plan who were mostly aware of their LDL-C levels indicate the need for gap-closure initiatives.

View details for DOI 10.1161/JAHA.119.015807

View details for PubMedID 32319337

Delisting STAP1: The Rise and Fall of a Putative Hypercholesterolemia Gene. Arteriosclerosis, thrombosis, and vascular biology Hegele, R. A., Knowles, J. W., Horton, J. D. 2020; 40 (4): 847–49 More

View details for DOI 10.1161/ATVBAHA.120.314006

View details for PubMedID 32208993

Association of insulin resistance, from mid-life to late-life, with aortic stiffness in late-life: the Atherosclerosis Risk in Communities Study. Cardiovascular diabetology Poon, A. K., Meyer, M. L., Tanaka, H., Selvin, E., Pankow, J., Zeng, D., Loehr, L., Knowles, J. W., Rosamond, W., Heiss, G. 2020; 19 (1): 11 More

Abstract

BACKGROUND: Insulin resistance may contribute to aortic stiffening that leads to end-organ damage. We examined the cross-sectional association and prospective association of insulin resistance and aortic stiffness in older adults without diabetes.METHODS: We analyzed 2571 men and women at Visit 5 (in 2011-2013), and 2350 men and women at repeat examinations from baseline at Visit 1 (in 1987-1989) to Visit 5 (in 2011-2013). Linear regression was used to estimate the difference in aortic stiffness per standard unit of HOMA-IR, TG/HDL-C, and TyG at Visit 5. Linear mixed effects were used to assess if high, as opposed to non-high, aortic stiffness (>75th percentile) was preceded by a faster annual rate of change in log-HOMA-IR, log-TG/HDL-C, and log-TyG from Visit 1 to Visit 5.RESULTS: The mean age of participants was 75years, 37% (n=957) were men, and 17% (n=433) were African American. At Visit 5, higher HOMA-IR, higher TG/HDL-C, and higher TyG were associated with higher aortic stiffness (16cm/s per SD (95% CI 6, 27), 29cm/s per SD (95% CI 18, 40), and 32cm/s per SD (95% CI 22, 42), respectively). From Visit 1 to Visit 5, high aortic stiffness, compared to non-high aortic stiffness, was not preceded by a faster annual rate of change in log-HOMA-IR from baseline to 9years (0.030 (95% CI 0.024, 0.035) vs. 0.025 (95% CI 0.021, 0.028); p=0.15) or 9years onward (0.011 (95% CI 0.007, 0.015) vs. 0.011 (95% CI 0.009, 0.013); p=0.31); in log-TG/HDL-C from baseline to 9years (0.019 (95% CI 0.015, 0.024) vs. 0.024 (95% CI 0.022, 0.026); p=0.06) or 9years onward (-0.007 (95% CI -0.010, -0.005) vs. -0.009 (95% CI -0.010, -0.007); p=0.08); or in log-TyG from baseline to 9years (0.002 (95% CI 0.002, 0.003) vs. 0.003 (95% CI 0.003, 0.003); p=0.03) or 9years onward (0 (95% CI 0, 0) vs. 0 (95% CI 0, 0); p=0.08).CONCLUSIONS: Among older adults without diabetes, insulin resistance was associated with aortic stiffness, but the putative role of insulin resistance in aortic stiffness over the life course requires further study.

View details for DOI 10.1186/s12933-020-0986-y

View details for PubMedID 31992297

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After AcuteCoronary Syndrome. Journal of the American College of Cardiology Bittner, V. A., Szarek, M., Aylward, P. E., Bhatt, D. L., Diaz, R., Edelberg, J. M., Fras, Z., Goodman, S. G., Halvorsen, S., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Moriarty, P. M., Moryusef, A., Pordy, R., Roe, M. T., Sinnaeve, P., Tsimikas, S., Vogel, R., White, H. D., Zahger, D., Zeiher, A. M., Steg, P. G., Schwartz, G. G., ODYSSEY OUTCOMES Committees and Investigators 2020; 75 (2): 133–44 More

Abstract

BACKGROUND: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).OBJECTIVES: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).METHODS: One to 12months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.RESULTS: Baseline lipoprotein(a) levels (median: 21.2mg/dl; interquartile range [IQR]: 6.7 to 59.6mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0mg/dl (IQR: 0 to 13.5mg/dl), corrected LDL-C by 51.1mg/dl (IQR: 33.7 to 67.2mg/dl), and reduced the risk of MACE (hazardratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95%CI: 0.990 to 0.999; p=0.0081).CONCLUSIONS: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluationof Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

View details for DOI 10.1016/j.jacc.2019.10.057

View details for PubMedID 31948641

Cardiorespiratory Fitness, Body-Mass Index, and Markers of Insulin Resistance in Apparently Healthy Women and Men. The American journal of medicine Clarke, S. L., Reaven, G. M., Leonard, D., Barlow, C. E., Haskell, W. L., Willis, B. L., DeFina, L., Knowles, J. W., Maron, D. J. 2020 More

Abstract

BACKGROUND: Insulin resistance may be present in healthy adults and is associated poor health outcomes. Obesity is a risk factor for insulin resistance, but most obese adults do not have insulin resistance. Fitness may be protective, but the association between fitness, weight, and insulin resistance has not been studied in a large population of healthy adults.METHODS: A cross-sectional analysis of cardiorespiratory fitness, body-mass index, and markers of insulin resistance was performed. Study participants were enrolled at the Cooper Clinic (Dallas, Texas). The analysis included 19,263 women and 48,433 men with no history of diabetes or cardiovascular disease. Cardiorespiratory fitness was measured using exercise treadmill testing. Impaired fasting glucose (100-125 mg/dL) and elevated fasting triglycerides (≥150 mg/dL) were used as a markers of insulin resistance.RESULTS: Among normal weight individuals, poor fitness was associated with a 2.2 (1.4-3.6; p=0.001) fold higher odds of insulin resistance in women and a 2.8 (2.1-3.6; p<0.001) fold higher odds in men. The impact of fitness remained significant for overweight and obese individuals, with the highest risk group being the unfit obese. Among obese women, the odds ratio for insulin resistance was 11.0 (8.7-13.9; p<0.001) for fit and 20.3 (15.5-26.5; p<0.001) for unfit women. Among obese men, the odds ratio for insulin resistance was 7.4 (6.7-8.2; p<0.001) for fit and 12.9 (11.4-14.6; p<0.001) for unfit men.CONCLUSION: Independent of weight, poor fitness is associated with risk of insulin resistance. Obese individuals, particularly women, may benefit from the greatest absolute risk reduction by achieving moderate fitness.

View details for DOI 10.1016/j.amjmed.2019.11.031

View details for PubMedID 31926863

FAM13A affects body fat distribution and adipocyte function. Nature communications Fathzadeh, M. n., Li, J. n., Rao, A. n., Cook, N. n., Chennamsetty, I. n., Seldin, M. n., Zhou, X. n., Sangwung, P. n., Gloudemans, M. J., Keller, M. n., Attie, A. n., Yang, J. n., Wabitsch, M. n., Carcamo-Orive, I. n., Tada, Y. n., Lusis, A. J., Shin, M. K., Molony, C. M., McLaughlin, T. n., Reaven, G. n., Montgomery, S. B., Reilly, D. n., Quertermous, T. n., Ingelsson, E. n., Knowles, J. W. 2020; 11 (1): 1465 More

Abstract

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.

View details for DOI 10.1038/s41467-020-15291-z

View details for PubMedID 32193374

Women Living with Familial Hypercholesterolemia: Challenges and Considerations Surrounding Their Care. Current atherosclerosis reports Balla, S. n., Ekpo, E. P., Wilemon, K. A., Knowles, J. W., Rodriguez, F. n. 2020; 22 (10): 60 More

Abstract

To highlight the gender-based differences in presentation and disparities in care for women with familial hypercholesterolemia (FH).Women with FH experience specific barriers to care including underrepresentation in research, significant underappreciation of risk, and interrupted therapy during childbearing. National and international registry and clinical trial data show significant healthcare disparities for women with FH. Women with FH are less likely to be on guideline-recommended high-intensity statin medications and those placed on statins are more likely to discontinue them within their first year. Women with FH are also less likely to be on regimens including non-statin agents such as PCSK9 inhibitors. As a result, women with FH are less likely to achieve target low-density lipoprotein cholesterol (LDL-C) targets, even those with prior atherosclerotic cardiovascular disease (ASCVD). FH is common, under-diagnosed, and under-treated. Disparities of care are more pronounced in women than men. Additionally, FH weighs differently on women throughout the course of their lives starting from choosing contraceptives as young girls along with lipid-lowering therapy, timing pregnancy, choosing breastfeeding or resumption of therapy, and finally deciding goals of care during menopause. Early identification and appropriate treatment prior to interruptions of therapy for childbearing can lead to marked reduction in morbidity and mortality. Women access care differently than men and increasing awareness among all providers, especially cardio-obstetricians, may improve diagnostic rates. Understanding the unique challenges women with FH face is crucial to close the gaps in care they experience.

View details for DOI 10.1007/s11883-020-00881-5

View details for PubMedID 32816232

Mitochondrial dysfunction, insulin resistance and potential genetic implications. Endocrinology Sangwung, P. n., Petersen, K. F., Shulman, G. I., Knowles, J. W. 2020 More

Abstract

Insulin resistance, IR, is fundamental to the development type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. IR has both heritable and environmental determinants centered on energy storage and metabolism. Recent insights from human genetic studies, coupled with comprehensive in vivo and ex vivo metabolic studies in humans and rodents have highlighted the critical role of reduced mitochondrial function as a predisposing condition for ectopic lipid deposition and IR. These studies support the hypothesis that reduced mitochondrial function, particularly in insulin responsive tissues such as skeletal muscle, white adipose tissue, and liver is inextricably linked to tissue and whole body IR through effects on cellular energy balance. Here we discuss these findings as well as address potential mechanisms that serve as the nexus between mitochondrial malfunction and IR.

View details for DOI 10.1210/endocr/bqaa017

View details for PubMedID 32060542

Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program. Stem cell research Kanchan, K. n., Iyer, K. n., Yanek, L. R., Carcamo-Orive, I. n., Taub, M. A., Malley, C. n., Baldwin, K. n., Becker, L. C., Broeckel, U. n., Cheng, L. n., Cowan, C. n., D'Antonio, M. n., Frazer, K. A., Quertermous, T. n., Mostoslavsky, G. n., Murphy, G. n., Rabinovitch, M. n., Rader, D. J., Steinberg, M. H., Topol, E. n., Yang, W. n., Knowles, J. W., Jaquish, C. E., Ruczinski, I. n., Mathias, R. A. 2020; 46: 101803 More

Abstract

Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined the structural integrity of 506 hiPSC lines as determined by copy number variations (CNVs). We observed that 149 hiPSC lines acquired 258 CNVs relative to donor DNA. We identified six recurrent regions of CNVs on chromosomes 1, 2, 3, 16 and 20 that overlapped with cancer associated genes. Furthermore, the genes mapping to regions of acquired CNVs show an enrichment in cancer related biological processes (IL6 production) and signaling cascades (JNK cascade & NFκB cascade). The genomic region of instability on chr20 (chr20q11.2) includes transcriptomic signatures for cancer associated genes such as ID1, BCL2L1, TPX2, PDRG1 and HCK. Of these HCK shows statistically significant differential expression between carrier and non-carrier hiPSC lines. Overall, while a low level of genomic instability was observed in the NextGen generated hiPSC lines, the observation of structural instability in regions with known cancer associated genes substantiates the importance of systematic evaluation of genetic variations in hiPSCs before using them as disease/research models.

View details for DOI 10.1016/j.scr.2020.101803

View details for PubMedID 32442913

RNA Interference Targeting Apolipoprotein C-III Results in Deep and Prolonged Reductions in Plasma Triglycerides Schwabe, C., Scott, R., Sullivan, D. R., Baker, J., Clifton, P., Hamilton, J., Given, B., Melquist, S., Knowles, J., Hegele, R. A., Ballantyne, C. M. LIPPINCOTT WILLIAMS & WILKINS. 2019: E987 More

View details for Web of Science ID 000508228600058

RNA Interference Targeting Hepatic Angiopoietin-Like Protein 3 Results in Prolonged Reductions in Plasma Triglycerides and LDL-C in Human Subjects Watts, G. F., Schwabe, C., Scott, R., Gladding, P., Sullivan, D. R., Baker, J., Clifton, P., Hamilton, J., Given, B., Melquist, S., Knowles, J., Hegele, R. A., Ballantyne, C. M. LIPPINCOTT WILLIAMS & WILKINS. 2019: E987–E988 More

View details for Web of Science ID 000508228600059

Precision screening for familial hypercholesterolaemia: a machine learning study applied to electronic health encounter data. The Lancet. Digital health Myers, K. D., Knowles, J. W., Staszak, D., Shapiro, M. D., Howard, W., Yadava, M., Zuzick, D., Williamson, L., Shah, N. H., Banda, J. M., Leader, J., Cromwell, W. C., Trautman, E., Murray, M. F., Baum, S. J., Myers, S., Gidding, S. S., Wilemon, K., Rader, D. J. 2019; 1 (8): e393-e402 More

Abstract

Cardiovascular outcomes for people with familial hypercholesterolaemia can be improved with diagnosis and medical management. However, 90% of individuals with familial hypercholesterolaemia remain undiagnosed in the USA. We aimed to accelerate early diagnosis and timely intervention for more than 1·3 million undiagnosed individuals with familial hypercholesterolaemia at high risk for early heart attacks and strokes by applying machine learning to large health-care encounter datasets.We trained the FIND FH machine learning model using deidentified health-care encounter data, including procedure and diagnostic codes, prescriptions, and laboratory findings, from 939 clinically diagnosed individuals with familial hypercholesterolaemia (395 of whom had a molecular diagnosis) and 83 136 individuals presumed free of familial hypercholesterolaemia, sampled from four US institutions. The model was then applied to a national health-care encounter database (170 million individuals) and an integrated health-care delivery system dataset (174 000 individuals). Individuals used in model training and those evaluated by the model were required to have at least one cardiovascular disease risk factor (eg, hypertension, hypercholesterolaemia, or hyperlipidemia). A Health Insurance Portability and Accountability Act of 1996-compliant programme was developed to allow providers to receive identification of individuals likely to have familial hypercholesterolaemia in their practice.Using a model with a measured precision (positive predictive value) of 0·85, recall (sensitivity) of 0·45, area under the precision-recall curve of 0·55, and area under the receiver operating characteristic curve of 0·89, we flagged 1 331 759 of 170 416 201 patients in the national database and 866 of 173 733 individuals in the health-care delivery system dataset as likely to have familial hypercholesterolaemia. Familial hypercholesterolaemia experts reviewed a sample of flagged individuals (45 from the national database and 103 from the health-care delivery system dataset) and applied clinical familial hypercholesterolaemia diagnostic criteria. Of those reviewed, 87% (95% Cl 73-100) in the national database and 77% (68-86) in the health-care delivery system dataset were categorised as having a high enough clinical suspicion of familial hypercholesterolaemia to warrant guideline-based clinical evaluation and treatment.The FIND FH model successfully scans large, diverse, and disparate health-care encounter databases to identify individuals with familial hypercholesterolaemia.The FH Foundation funded this study. Support was received from Amgen, Sanofi, and Regeneron.

View details for DOI 10.1016/S2589-7500(19)30150-5

View details for PubMedID 33323221