Research ArticleVariant adiponutrin (PNPLA3) represents a common fibrosis risk gene: Non-invasive elastography-based study in chronic liver disease

Background & AimsRecent genome-wide association studies have identified the variant p.I148M of the adiponutrin gene PNPLA3 as a risk factor for developing severe forms of non-alcoholic and alcoholic liver diseases. The risk allele confers an increased risk for fatty liver disease and elevated serum aminotransferase activities reflecting liver injury. In the current elastography-based study, we investigate variant adiponutrin as genetic determinant of liver fibrosis, the hallmark of all chronic liver diseases.MethodsIn this observational cross-sectional study, we staged 899 patients with different chronic liver diseases non-invasively by transient elastography (Fibroscan) and genotyped them for variant adiponutrin (rs738409) by PCR-based assays. A subgroup of 229 patients consented to percutaneous liver biopsy, validating the accuracy of elastography in staging fibrosis (ρ = 0.743, p <0.01).ResultsCarriers of distinct p.I148M adiponutrin genotypes display significant (p = 0.017) differences in liver stiffness determined by elastography. In particular, individuals carrying the allele [G] are at higher risk of developing liver cirrhosis defined by stiffness values ⩾13.0 kPa (OR = 1.56, p = 0.005). Of note, the PNPLA3 risk variant advances fibrosis in the total cohort as well as in the subgroups of patients with viral hepatitis and non-viral liver diseases and contributes 16% of the total cirrhosis risk.ConclusionsThe adiponutrin risk variant is a common genetic determinant of progressive liver fibrosis. Our results underpin non-invasive follow-up for individuals with chronic liver disease at-risk for developing advanced fibrosis and cirrhosis.