Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease.

Abstract

Hepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD. We analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399). The prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p<0.001). The prevalence of patients with advanced fibrosis (stages 3-4) was higher for PNPLA3 genotype CG/GG than CC (p=0.048) and for TLL1 genotype AT/TT than AA (p=0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p=0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p=0.004], serum albumin (OR 0.247, p=0.032), and genetic high risk (OR 2.632, p=0.026) as predictors of advanced fibrosis. In Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.