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

• Published in: Hepatology (Baltimore, Md.) Vol. 58; no. 3; pp. 966 - 975
• Main Authors: Palmer, Nicholette D., Musani, Solomon K., Yerges‐Armstrong, Laura M., Feitosa, Mary F., Bielak, Lawrence F., Hernaez, Ruben, Kahali, Bratati, Carr, J. Jeffrey, Harris, Tamara B., Jhun, Min A., Kardia, Sharon L.R., Langefeld, Carl D., Mosley, Thomas H., Norris, Jill M., Smith, Albert V., Taylor, Herman A., Wagenknecht, Lynne E., Liu, Jiankang, Borecki, Ingrid B., Peyser, Patricia A., Speliotes, Elizabeth K.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-09-2013
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; African Americans; Aged; Black People - ethnology; Black People - genetics; Chondroitin Sulfate Proteoglycans - genetics; Cohort Studies; Diet; Fatty Liver - ethnology; Fatty Liver - genetics; Female; Gene Frequency - genetics; Genealogy; Genetic Predisposition to Disease - ethnology; Genetic Predisposition to Disease - genetics; Genetic Variation - genetics; Hepatology; Hispanic or Latino - ethnology; Hispanic or Latino - genetics; Humans; Lectins, C-Type - genetics; Lipase - genetics; Liver cirrhosis; Liver diseases; Lysophospholipase - genetics; Male; Membrane Proteins - genetics; Middle Aged; Nerve Tissue Proteins - genetics; Neurocan; Non-alcoholic Fatty Liver Disease; Phosphoprotein Phosphatases - genetics; White People - ethnology; White People - genetics
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.26440

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)