PNPLA3 Rs738409 C>G Variant Predicts Liver-Related Outcomes in Patients with Non-Alcoholic Fatty Liver Disease

Abstract

Background: Patients with NAFLD are at higher risk of developing liver-related complications -liver decompensation(LD) and hepatocellular carcinoma (HCC), including death-. A single nucleotide polymorphism in PNPLA3 gene is associated with a higher prevalence of liver damage and HCC, but prospective date are not available. We aimed to assess whether the common rs738409 variant in PNPLA3 gene can predict the occurrence of liver-related events and death in a large cohort of NAFLD patients. Methods: We considered 471 consecutive Italian individuals with histological diagnosis of NAFLD or clinical diagnosis of compensated NAFLD-related cirrhosis, prospectively followed for at least 6 months. The occurrence of hepatic and extrahepatic outcomes was recorded (LD and HCC; cardiovascular events and extrahepatic cancers, overall and liver-related death). The rs738409 G>C polymorphisms was genotyped by TaqMan assay. Findings: During a median follow-up of 64.6 months 26 LD, 13 HCC and 16 deaths (12 liver-related) were recorded. All liver-related events including liver-related death, occurred in patients with F3 fibrosis or cirrhosis. After adjusting for clinico-metabolic and histological risk factors PNPLA3 C>G variant was associated with a higher risk of LD(HR 2.10,95%C.I.1.03-4.29, p=0.04), HCC (HR 2.68,95%C.I.1.01-7.26, p=0.04) and liver-related death (HR 3.64, 5%C.I.1.18-11.2, p=0.02) by multivariate Cox regression analysis. In the subgroup of 162 patients with F3 fibrosis or cirrhosis we confirmed the independent association of PNPLA3 variant with LD (HR 2.00,95%C.I.1.01-3.97, p=0.04), HCC (HR 2.66,95%C.I.1.02-7.13, p=0.04) and liver-related death (HR 3.64,95%C.I.1.18-11.2, p=0.02). No association was found between PNPLA3 genotype and cardiovascular events, extrahepatic cancers and overall mortality. Interpretations: Patients carrying PNPLA3 rs738409 G>C variant are at higher risk of developing liver-related events and death. Funding: None. Declaration of Interest: None. Ethical Approval: The study was carried out in accordance with the principles of the Helsinki Declaration, and with local and national laws. Approval was obtained from the AOUP “Giaccone” of Palermo.