NICHOLETTE ALLRED, CHINMAY RAUT, YANHUA CHEN, ANTONINO OLIVERI, JEFFREY O'CONNELL, KATHLEEN RYAN, JEROME I. ROTTER, STEPHEN S. RICH, AARON HAKIM, PATRICIA PEYSER, LAWRENCE F. BIELAK, CHING-TI LIU, JAMES G. TERRY, MYRIAM FORNAGE, LYNNE E. WAGENKNECHT, ELIZABETH K. SPELIOTES, NHLBI TRANS-OMICS FOR PRECISION MEDICINE (TOPMED)PROGRAM, GOLD CONSORTIUM
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引用次数: 0
Abstract
Introduction and Objective: Steatotic liver disease, formerly called non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease worldwide; yet, few effective methods for prevention/treatment exist making it one of the biggest unmet public health needs of our time. To date, genetic studies have been limited to identifying common variants in predominantly European-ancestry populations or focused on surrogate phenotypes, e.g. liver enzymes, identifying association with comorbidities. Here we present a multi-ancestry whole genome sequencing (WGS) association study to discover rare variants associated with imaging-measured hepatic steatosis. Methods: Study-, ancestry- and sex-stratified association analyses were conducted using SAIGEgds in nine studies with imaging-measured hepatic steatosis adjusted for age, sex, alcoholic drinks per week and principal component estimates of admixture. Stratified results were meta-analyzed using a fixed-effects model. Cochran’s Q-test and the I2 metric were used to estimate heterogeneity. Results: Meta-analyses included 23,156 European, African, Hispanic and Chinese ancestry individuals and identified five significant loci (P<5x10-08): PNPLA3, PPP1R3B, HAPLN4, intergenic region on chr14 and F11-AS1. Nine additional variants trended toward association (P<5x10-07). Sex-stratified meta-analyses revealed additional associations in an intergenic region on chr10, RP11-115J16.1 and UBE3B. Variants in RP11-115J16.1 remained significant in European ancestry samples. Significantly associated variants in SLC2A1-AS1 and LINC01684 were novel loci in African Americans. Conclusion: Taken together, multi-ancestry analysis of imaging-measured hepatic steatosis using WGS replicated previously associated loci and identified novel sex- and ancestry-specific loci. Functional studies are underway to determine the biological impact of these findings. Disclosure N. Allred: None. C. Raut: None. Y. Chen: None. A. Oliveri: None. J. O'Connell: None. K. Ryan: None. J.I. Rotter: None. S.S. Rich: None. A. Hakim: None. P. Peyser: None. L.F. Bielak: None. C. Liu: None. J.G. Terry: None. M. Fornage: None. L.E. Wagenknecht: None. E.K. Speliotes: Other Relationship; University of Michigan. Funding National Institute of Diabetes and Digestive Kidney Disease (R01 DK128871)
期刊介绍:
Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes.
However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.