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

Background & Aims: Recent genome-wide association studies have identified the variant p.I148M of the adiponutrin gene PNPLA3 as a risk factor for developing severe forms of nonalcoholic 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. Methods: In 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 (rho = 0.743, p <0.01). Results: Carriers 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. Conclusions: The 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. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.