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

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=3124) 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 31.8/28.9kg/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. Conclusions We show for the first time that multiple genetic variants are associated with hepatic steatosis across ancestries and explain a substantial proportion of the genetic predisposition in African and Hispanic Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.

Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease

“…Although the direction of the association is protective and the variant is rarer, the size effect was marked, making it very similar to that of the PNPLA3 I148M variant on these three major outcomes. Despite previous contrasting evidence,8, 9, 10, 11, 12, 13 these novel data lend strong support to the hypothesis that the PPP1R3B variation does protect against hepatic fat accumulation, at least in at‐risk individuals. Furthermore, they support the notion that steatosis is a major driver of liver disease progression to fibrosis7 and HCC18 in individuals with NAFLD.…”

“…PPP1R3B encodes for a protein involved in glycogen synthesis 9. Subsequent studies have been consistent with the hypothesis that the rs4240624 variant, which is located 175 kilobase (kb) upstream of the PPP1R3B coding region, associates with reduced fat as estimated by ultrasonography10, 11 and with increased hepatic glycogen content 12. However, when liver fat was directly measured by histology, the association with the PPP1R3B variation was not confirmed 8, 13.…”

Association of polymorphisms in <i>GCKR</i> and <i>TRIB1</i> with nonalcoholic fatty liver disease and metabolic syndrome traits

“…The A-allele of rs780094 in GCKR was associated with NAFLD in subjects of European descent [11,28,29]. No association between the A-allele of rs780094 and NAFLD was observed in African American and Hispanic Americans [28,29]. A study in Asian populations (Indian, Malay, and Chinese) was not conclusive, due to small sample size [30].…”

Beyond the Genetics of HDL: Why Is HDL Cholesterol Inversely Related to Cardiovascular Disease?

“…The gene encoding for glycogentargeting PP1 (protein phosphatase 1) subunit G(L) has also been associated with type 2 diabetes and maturity-onset diabetes of the young but sequence variants at the PPP1R3B locus were not found to be related to diabetes in mostly Caucasian families (Dunn et al 2006). Other studies proposed a role for this gene in inflammation (Dehghan et al 2011), Alzheimer's disease (Kamboh et al 2012), and hepatic steatosis (Palmer et al 2013). As for TTC39B, there are no mechanistic studies that have revealed insight into how PPP1R3B gene products may affect lipid metabolism.…”