Interaction between PNPLA3 I148M variant and age at infection in determining fibrosis progression in chronic hepatitis C

BACKGROUND AND AIMS: The PNPLA3 I148M sequence variant favors hepatic lipid accumulation and confers susceptibility to hepatic fibrosis and hepatocellular carcinoma. The aim of this study was to estimate the effect size of homozygosity for the PNPLA3 I148M variant (148M/M) on the fibrosis progression rate (FPR) and the interaction with age at infection in chronic hepatitis C (CHC). METHODS: FPR was estimated in a prospective cohort of 247 CHC patients without alcohol intake and diabetes, with careful estimation of age at infection and determination of fibrosis stage by Ishak score. RESULTS: Older age at infection was the strongest determinant of FPR (p<0.0001). PNPLA3 148M/M was associated with faster FPR in individuals infected at older age (above the median, 21 years; -0.64\ub10.2, n\u200a=\u200a8 vs. -0.95\ub10.3, n\u200a=\u200a166 log10 FPR respectively; p\u200a=\u200a0.001; confirmed for lower age thresholds, p<0.05), but not in those infected at younger age (p\u200a=\u200ans). The negative impact of PNPLA3 148M/M on fibrosis progression was more marked in subjects at risk of altered hepatic lipid metabolism (those with grade 2-3 steatosis, genotype 3, and overweight; p