Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals
Journal
American Journal of Clinical Nutrition
Journal Volume
99
Journal Issue
4
Pages
869-874
Date Issued
2014
Author(s)
Abstract
Background: A genome-wide association study identified variants in or near patatin-like phospholipase domain-containing-3 (PNPLA3), neurocan (NCAN), lysophospholipase-like 1 (LYPLAL1), glucokinase regulatory protein (GCKR), and protein phosphatase 1 regulatory subunit 3b (PPP1R3B) that were strongly associated with nonalcoholic fatty liver disease (NAFLD) in adults of European ancestry. Objective: We examined these genetic variants in obese children and tested whether their effects on NAFLD are significant in the Taiwanese Han Chinese population. Design: We genotyped PNPLA3 rs738409, NCAN rs2228603, LYPLAL1 rs12137855, GCKR rs780094, and PPP1R3B rs4240624 in 797 obese children aged 7-18 y. NAFLD was identified by liver ultrasonography. We analyzed the effect of these genetic variants on NAFLD. Results: NAFLD was identified in 24% of the recruited obese children. We found significant associations with NAFLD at variants in PNPLA3 and GCKR but not in NCAN, LYPLAL1 , and PPP1R3B. Multiple logistic regression analysis showed that, after control for the effects of age- and sex-adjusted body mass index, waist-to-hip ratio, sex, and PNPLA3 rs738409 polymorphism, the variant GCKR rs780094 TT genotype independently increased the OR of NAFLD by 1.997 (95% CI: 1.196, 3.335; P = 0.008) compared with the CC genotype. Subjects with the variant GCKR rs780094 TT genotype had a higher mean serum alanine aminotransferase concentration than did those with the CC genotype (30.8 ± 34.7 compared with 22.2 ± 18.6 IU/L; P = 0.01). Conclusions: By studying the genetic variants of obese Taiwanese children, we confirmed that the genetic variants in GCKR rs780094 and PNPLA3 rs738409, but not in NCAN rs2228603, LYPLAL1 rs12137855, and PPP1R3B rs4240624, are associated with an increased risk of NAFLD. GCKR and PNPLA3 variants are the common genetic factors that may confer susceptibility to NAFLD in obese individuals across multiple ethnic groups. This trial was registered at clinicaltrials.gov as NCT00274183. ? 2014 American Society for Nutrition.
SDGs
Other Subjects
alanine aminotransferase; adolescent; alanine aminotransferase blood level; article; body mass; child; controlled study; disease predisposition; DNA polymorphism; echography; female; gene; gene frequency; genetic risk; genetic variability; genotype; glucokinase regulatory protein gene; human; lysophospholipase like 1 gene; major clinical study; male; neurocan gene; nonalcoholic fatty liver; obesity; patatin like phospholipase domain containing 3 gene; protein phosphatase 1 regulatory subunit 3b gene; school child; waist hip ratio; Adaptor Proteins, Signal Transducing; Adolescent; Alleles; Asian Continental Ancestry Group; Body Mass Index; Child; Fatty Liver; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Insulin Resistance; Linkage Disequilibrium; Lipase; Liver; Male; Membrane Proteins; Obesity; Polymorphism, Single Nucleotide; Taiwan
Publisher
American Society for Nutrition
Type
journal article