Characterization of european ancestry nonalcoholic fatty liver disease-associated variants in individuals of african and hispanic descent

Authors


  • Potential conflict of interest: Nothing to report.

  • Support for the Jackson Heart Study was provided by the National Heart Lung and Blood Institute and the National Center on Minority Health and Health Disparities grants N01-HC95170, N01-HC95171, and N01-HC95172. Support for the Insulin Resistance Atherosclerosis Family Study was provided by the National Heart, Lung and Blood Institute grants 5R01HL060944, 5R01HL061019, 5R01HL060919, 5R01HL060894, and 5R01HL061210. Support for the Genetic Epidemiology Network of Arteriopathy was provided by the National Institutes of Health, grant numbers HL085571, HL087660, and HL100245 from National Heart, Lung, Blood Institute. Support for the Family Heart Study was provided by the National Heart, Lung and Blood Institute grant 5R01HL08770003 and by the National Institute of Diabetes and Digestive and Kidney Diseases grant 5R01DK075681. IRASFS genotyping was carried out with funds from the Department of Internal Medicine at the University of Michigan. Analysis was partially supported by the Mid-Atlantic Nutrition Obesity Research Center (P30 DK072488) from the National Institute of Diabetes and Digestive and Kidney Diseases. In addition, we thank the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK081350, to N.D.P.), the American Diabetes Association Mentor-Based Postdoctoral Fellowship Program (7-07-MN-08, RH), the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK080145 to E.K.S. and B.K.), the Doris Duke Charitable Foundation (Grant 2012067, to E.K.S. and B.K.), the Department of Internal Medicine and Biological Sciences Scholars Program at the University of Michigan (to E.K.S. and B.K.).

Address reprint requests to: Elizabeth K. Speliotes, M.D., Ph.D., MPH, University of Michigan, 6520 MSRBI, SPC 5682, 1150 W. Medical Center Drive, Ann Arbor MI 48109-5682, E-mail: espeliot@med.umich.edu, fax: 734-763-2535.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African- and/or Hispanic-Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age2, gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m2, respectively. Hepatic steatosis was 0.20-0.34 heritable in African- and Hispanic-American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1. Conclusion: Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African- and Hispanic-Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries. (Hepatology 2013;53:966–975)

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