The greater impact of PNPLA3 polymorphism on liver-related events in Japanese non-alcoholic fatty liver disease patients: A multicentre cohort study.

BACKGROUND & AIMS:PNPLA3 rs738409 has been associated with an increased risk of liver-related events in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the epidemiology of NAFLD and the impact of PNPLA3 on prognosis in Japan. METHODS:A longitudinal multicentre cohort study, the JAGUAR study, includes 1550 patients with biopsy-proven NAFLD in Japan. We performed genetic testing and evaluated outcomes from this cohort. Liver-related events were defined as hepatocellular carcinoma (HCC) and decompensated liver cirrhosis events. RESULTS:During follow-up (median [range], 7.1 [1.0-24.0] years), 80 patients developed HCC, 104 developed liver-related events, and 59 died of any cause. The 5-year rate of liver-related events for each single-nucleotide polymorphism was 0.5% for CC, 3.8% for CG, and 5.8% for GG. Liver-related deaths were the most common (n = 28); only three deaths were due to cardiovascular disease. Multivariate analysis identified carriage of PNPLA3 CG/GG (hazard ratio [HR] 16.04, p = .006) and FIB-4 index >2.67 (HR 10.70, p < .01) as predictors of liver-related event development. No HCC or liver-related death was found among patients with PNPLA3 CC. There was a significantly increased risk of HCC, liver-related events, and mortality for CG/GG versus CC, but no difference between the CG and GG genotypes. CONCLUSIONS:In Japanese individuals, the main cause of death from NAFLD is liver-related death. The greater risk of liver-related events incurred by PNPLA3 G allele was shown in Japan. Risk stratification for NAFLD in Japan is best accomplished by integrating PNPLA3 with the FIB-4 index.