Association between rs738409 polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene and hepatocellular carcinoma susceptibility: Evidence from case-control studies

Objectives: Numerous studies have investigated the association between patatin-like phospholipase domain containing protein-3 (PNPLA3) rs738409 C > G polymorphism and the risk of hepatocellular carcinoma (HCC). However, the results are conflicting and inconclusive among different populations. Thus, a meta-analysis was performed to resolve this inconsistency. Methods: Potentially related studies were investigated in PubMed, Cochrane Library, EMBASE, and Chinese Biomedical Database (CBM) up to June 12, 2018. The odds ratio (OR) with a 95% confidence interval (CI) was used to explore the strength of the associations. Subgroup analysis was performed according to ethnicity and etiology of cases. Publication bias detection was conducted using Egger's test. Results: Fourteen case-control studies were included in this meta-analysis, reporting a total of 3527 HCC patients and 7184 controls. Overall results revealed that PNPLA3 rs738409 C > G polymorphism was associated with an increased risk of HCC in the populations studied with various types of etiology under allelic model (OR = 1.59, 95%CI: 1.20-2.10, P = 0.001), dominant model (OR = 1.55, 95%CI: 1.13-2.13, P = 0.007), homozygous model (OR = 2.76, 95%CI: 1.52-5.01, P = 0.001), heterozygous model (OR = 1.31, 95%CI: 1.01-1.69, P = 0.039), and recessive model (OR = 2.42, 95%CI: 1.51-3.87, P < 0.001). A significant increased risk was observed in patients with HCC related to alcoholic cirrhosis under all genetic models (C vs. G: OR = 3.35, 95%CI: 2.14-5.24, P < 0.001; CC vs.GG: OR = 11.02, 95%CI: 4.35-27.88, P < 0.001; CC vs. GC: OR = 2.75, 95%CI: 1.72-4.39, P < 0.001; GG vs. CC + CG: OR = 5.82, 95%CI: 2.93-11.57, P < 0.001; CG + GG vs. CC: OR = 4.08, 95%CI: 2.33-7.13, P < 0.001), with respect to specific etiology of HCC. A significant increased risk was also revealed in patients with HCC due to virus related cirrhosis under allelic model (OR = 1.19, 95%CI: 1.07-1.32, P = 0.001), dominant model (OR = 1.17, 95%CI: 1.02-1.35, P = 0.03), homozygous model (OR = 1.47, 95%CI: 1.17-1.85, P = 0.001), and recessive model (OR = 1.43, 95%CI: 1.15-1.76, P = 0.001). Subgroup analysis on ethnicity revealed that the polymorphism was associated with increased risk of HCC in Caucasians under allelic model (OR = 1.65, 95%CI: 1.12-2.45, P = 0.012), dominant model (OR = 1.63, 95%CI: 1.04-4.25, P = 0.035), homozygous model (OR = 2.88, 95%CI: 1.27-6.55, P = 0.012), and recessive model (OR = 2.48, 95%CI: 1.32-4.65, P = 0.005). Conclusions: Our study suggests a significant increased association between PNPLA3 rs738409 C > G polymorphism and HCC risk in the entire populations studied, especially in Caucasians. Therefore, PNPLA3 rs738409 C > G polymorphism may be a risk factor for virus and alcoholic-related HCC.