Genetic Variation in the Peroxisome Proliferator Activated Receptor-gamma Gene Is Associated with NAFLD and Its Histological Phenotypes

Abstract

Listen

Translate article

Purpose: Peroxisome proliferator activated receptor-gamma (PPAR-γ) is a nuclear receptor that regulates adipocyte differentiation, lipid metabolism and insulin sensitivity and is the molecular target for thiazolidinediones, agents that enhance sensitivity to insulin. Thus, it is a good candidate gene for NAFLD. The Ala12 variant of PPAR-γ has been associated with increased insulin sensitivity, lower body mass and protection from type 2 diabetes. A second polymorphism C1431T has been associated with increased body weight. Aim: To test the association of two PPAR-γ single nucleotide polymorphisms (SNP) with NAFLD and its histological sub-phenotypes. Methods: DNA was extracted from 158 archived, formalin-fixed liver biopsy specimens from patients with NAFLD and normal controls. Two SNPs of PPAR-γ (Pro12Ala and C1431T) were genotyped by Taqman assay using the Biotrove OpenArray system. PPAR-γ haplotypes were predicted using the program Dandelion, which employs the Expectation-Maximization (EM) algorithm to obtain maximum likelihood estimates of the haplotype frequencies and the probabilities of the observed haplo-genotypes for each individual. Results: DNA was successfully isolated and genotyped for 26 controls, 87 FL, and 45 NASH patients. For both SNPs tested, the minor allele frequencies were decreased in NAFLD compared to controls (10.8 vs 25% for C1431T, and 9.5 vs 17.3% for Pro12Ala). In subjects with NAFLD, the minor alleles were enriched in subjects with FL compared to those with NASH (12.5 vs 7.5% for C1431T and 13.3 vs 0.03% for Pro12Ala). Only variation in C1431T was associated with steatosis (P 0.03). Haplotype analysis revealed a haplotype consistent of both minor alleles (TG) that is present only in subjects with NAFLD but not in controls (2.7 vs 0%). This haplotype was also significantly associated with steatosis, fibrosis, ballooning and lobular inflammation under an additive genetic model. Conclusion: Genetic variation in PPAR-γ is associated with NAFLD and its histological phenotypes. A haplotype shows strong association with histological findings of NASH, and is more common in individuals with NAFLD than controls. This haplotype may influence the development of NASH and its characteristic inflammatory and fibrotic changes.