Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: Risk and prognosis prediction

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case–control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68–6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13–71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05–5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26–3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.

The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis

“…In addition to NAFLD and AFLD, the results of a recent meta-analysis reported by Trépo et al ( 46 ) indicate that the PNPLA3 rs738409 C>G polymorphism is signifi cantly associated with hepatocellular carcinoma in patients of European descent with cirrhosis. The GG genotype was also found to be associated with a higher risk of hepatocellular carcinoma in a US patient population ( 41 ). Taken together, our fi ndings and those from previously published reports demonstrate that the PNPLA3 rs738409 C>G polymorphism increases the risk of liver disease.…”

“…Other reports have examined the association between the PNPLA3 rs738409 C>G polymorphism and other forms of liver disease, most notably NAFLD, which leads to United States, Taiwan, China, Japan, or Malaysia (39)(40)(41)(42)(43). Indeed, in a Japanese study, Hotta et al ( 44 ) found that the risk of carrying the G allele was 0.44 in control patients and 0.60 in patients with NAFLD.…”

Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma

“…11–13 Overall survival (OS) was defined as the time between HCC diagnosis and death (as a result of all causes) or end of follow-up (censored observations). Underlying cirrhosis was determined by pathological findings (diagnostic biopsies) and by computed tomography scans.…”

An update on the validity of irisin assays and the link between irisin and hepatic metabolism

“…A third meta-analysis also indicated that the I148M polymorphism is associated with advanced fibrosis, but, most importantly, with greater risk of NASH-related hepatocellular carcinoma [13]. Notably, in a prospective cohort study, the PNPLA3 GG genotype was significantly associated with underlying cirrhosis in patients with hepatocellular carcinoma and represented an independent risk factor for death [14]. Apart from NAFLD, the same SNP plays a role in other liver diseases, including chronic hepatitis C, in which it is associated with steatosis, cirrhosis, lack of response to antiviral treatment and possibly hepatocellular carcinoma [15].…”