Association Between Variants in or Near PNPLA3, GCKR, and PPP1R3B With Ultrasound-Defined Steatosis Based on Data From the Third National Health and Nutrition Examination Survey

Abstract

BACKGROUND & AIMS A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. METHODS We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. RESULTS The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. CONCLUSIONS We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations.

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.…”

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…Contrary to other adipokines, adiponectin correlates negatively with BMI, insulin resistance, plasma TG, LDL-cholesterol, hepatic fat content and progression to NASH in NAFLD patients [38,123] . Adiponectin has been reported to be higher in women and in Caucasian compared with Asian or African individuals [123,124] . Adiponectin is known to have insulin-sensitising, antifibrogenic and anti-inflammatory properties.…”

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

“…Again, these rates can be influenced by genetic predisposition, as described later. In summary, NAFLD prevalence rates differ by ethnicity within the USA 1,[18][19][20][21] . The Hispanic population has the highest prevalence whereas African Americans are reported to have the lowest prevalence, despite hav ing higher prevalence of hypertension and obesity, both NAFLD risk factors.…”