Association between PNPLA3 rs738409 polymorphisms and risk of hepatocellular carcinoma and its development in patients with cirrhosis: a meta-analysis

Genetic variants of PNPLA3 have been implicated in hepatocellular carcinoma (HCC) susceptibility; however, published findings have been both conflicting and inconclusive. To obtain a more precise estimate of the association of the PNPLA3 rs738409 (C > G) polymorphism with the overall risk of HCC and in patients with cirrhosis, we performed a meta-analysis of nine eligible studies identified through an online search of Ovid, PubMed, EBSCO, the Cochrane Library, the Web of Science, the China National Knowledge Infrastructure, Wanfang, and Chinese Biomedicine databases. The studies comprised 1175 patients with HCC, 876 with cirrhosis, and 3026 healthy controls. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess associations, using fixed-effects models. Etiology subgroup and sensitivity analyses were also performed. Our results showed that rs738409 was associated with overall HCC risk and in patients with cirrhosis in the genetic contrast modes: G vs. C, GG + CG vs. CC, GG vs. CG + GG, and GG vs. CC. Stratification by etiology did not reveal any significant association between this polymorphism and hepatitis C virus (HCV)-related HCC in patients with HCV-related cirrhosis (P > 0.05). However, healthy individuals harboring two copies of the rs738409 G variant had a higher risk of HCC (GG vs. CC: OR = 4.40, 95% CI: 3.28-5.91) than those carrying a single G allele (CG vs. CC: OR = 1.62, 95% CI: 1.34-1.59); these significant association were also present in each subgroup. Furthermore, the association was more pronounced in alcohol vs. HCV-related HCC. The present meta-analysis suggests that the PNPLA3 rs738409 G allele is a risk factor for HCC except in patients with HCV-related cirrhosis, and that two copies of the rs738409 G variant conferred a higher risk for HCC in controls, especially for alcohol-related HCC. Further studies with a larger sample size are needed to ascertain the association in different ethnicities.