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

J Hepatol. 2011 Aug;55(2):299-306. doi: 10.1016/j.jhep.2010.10.042. Epub 2010 Dec 17.


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 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.

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 (ρ=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 ≥13.0kPa (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Chronic Disease
  • Cross-Sectional Studies
  • DNA Primers / genetics
  • Elasticity Imaging Techniques
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lipase / genetics*
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / pathology*
  • Liver Diseases / genetics
  • Liver Diseases / pathology
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Young Adult


  • DNA Primers
  • Membrane Proteins
  • Lipase
  • adiponutrin, human