Homozygosity for the PNPLA3/adiponutrin I148M polymorphism influences liver fibrosis in patients with Nonalcoholic Fatty Liver Disease

Background and Aims: Inherited factors play a major role in the predisposition to NAFLD, and the rs738409 C > G polymorphism of PNPLA3/adiponutrin , encoding for the I148M protein variant, has recently been recognized as a major determinant of liver fat content. The effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. Methods: We considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affect child with fibrotic NAFLD. Analyses were replicated in 321 UK patients. The rs738409 polymorphism was determined by Taqman assays. Liver histology was scored according to Kleiner. Hepatic expression of adiponutrin and genes regulating liver damage was assessed by real-time PCR in 52 patients. Results: The rs738409 GG genotype was more prevalent in patients than in controls (14% vs. 3%, adjusted OR 3.29, 95%CI 1.8–6.9), and in the family study the G allele was over-transmitted to affected children (p=0.001). In Italian patients, adiponutrin genotype influenced HDL cholesterol, ALT levels, and the expression of genes involved in the steatosis-related liver damage. Independently and in the whole series combined adiponutrin genotype was associated with steatosis grade > 1 (p=0.04), NASH (p=0.0002), and fibrosis stage > 1 (p=0.0001) independently of age, BMI, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes. Conclusions: In patients with NAFLD, adiponutrin I148M genotype is associated with the severity of steatosis and fibrosis and the presence of NASH