Inherited factors play a major role in the predisposition to
nonalcoholic fatty liver disease (
NAFLD), and the rs738409 C-->G polymorphism of PNPLA3/
adiponutrin, encoding for the
isoleucine-to-
methionine substitution at residue 148 (I148M)
protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of
liver fibrosis in patients with
NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with
NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P = 0.001). In Italian and United Kingdom patients,
adiponutrin genotype influenced
alanine aminotransferase levels and the severity of steatosis.
Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule
Fas ligand. In the whole series combined,
adiponutrin genotype was associated with steatosis grade >1 (OR = 1.35, 95% CI = 1.04-1.76),
nonalcoholic steatohepatitis (OR = 1.5, 95% CI = 1.12-2.04), and
fibrosis stage >1 (OR = 1.5, 95% CI = 1.09-2.12), independent of age, body mass index, and diabetes.
Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes.
CONCLUSION: