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

PLoS One. 2014 Aug 29;9(8):e106022. doi: 10.1371/journal.pone.0106022. eCollection 2014.

Abstract

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±0.2, n = 8 vs. -0.95±0.3, n = 166 log10 FPR respectively; p = 0.001; confirmed for lower age thresholds, p<0.05), but not in those infected at younger age (p = ns). 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<0.05). At multivariate analysis, PNPLA3 148M/M was associated with FPR (incremental effect 0.08±0.03 log10 fibrosis unit per year; p = 0.022), independently of several confounders, and there was a significant interaction between 148M/M and older age at infection (p = 0.025). The association between 148M/M and FPR remained significant even after adjustment for steatosis severity (p = 0.032).

Conclusions: We observed an interaction between homozygosity for the PNPLA3 I148M variant and age at infection in determining fibrosis progression in CHC patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Disease Progression
  • Fatty Liver / complications
  • Fatty Liver / genetics
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Hepatitis C, Chronic / complications
  • Hepatitis C, Chronic / genetics*
  • Humans
  • Lipase / genetics*
  • Lipid Metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Multivariate Analysis
  • Mutation, Missense*
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Severity of Illness Index
  • Young Adult

Substances

  • Membrane Proteins
  • Lipase
  • adiponutrin, human

Grants and funding

This manuscript was supported by Ricerca Corrente Fondazione IRCCS Ca' Granda (Institutional core funds; no grant number is available), and Associazione Malattie Metaboliche del Fegato ONLUS (non-profit organization for the study and the cure of metabolic liver diseases). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.