Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases

Abstract

Background: The aim of this study was to evaluate any association between a single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409, C>G) and the development and prognosis in patients with hepatocellular carcinoma (HCC). Materials and Methods: Two hundred heathy controls and 388 HCC cases were included: 211 with HBV, 98 patients with HCV, 29 with alcoholic steatohepatitis (ASH) and 52 with non-alcoholic steatohepatitis (NASH). The SNP was determined by real-time PCR based on TaqMan assays. Results: The prevalence of rs738409 genotypes CC, CG and GG in controls was 91 (45.5%), 88 (44.0%), and 21 (10.5%), respectively, while the corresponding genotypes in all patients with HCC was 158 (40.7%), 178 (45.9%), and 52 (13.4%). The GG genotype had significantly higher distribution in patients with ASH/NASH-related HCC compared with controls (OR=2.34, 95% CI=1.16-4.71, P=0.018), and viral-related HCC cases (OR=2.15, 95% CI=1.13-4.08, P=0.020). However, the frequency of the GG genotype was similar between controls and patients with viral-related HCC. At initial diagnosis, HBV-related HCC were larger and at more advanced BCLC stage than the other HCC groups. There were no significant differences between the GG and non-GG groups regarding clinical characteristics, tumor stage and overall survival. Conclusions: These data suggest an influence of the PNPLA3 polymorphism on the occurrence of HCC in patients with ASH/NASH but not among those with chronic viral hepatitis. However, the polymorphism was not associated with the prognosis of HCC.

PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases

“…In contrast, the potential association between PNPLA3 rs738409 and HCC risk in patients with HCV‐related cirrhosis remains controversial . The association between this variant and HCC risk in HCV‐related cirrhosis was either marginal in our case–control study or negative in our prospective cohort.…”

“…In contrast, the potential association between PNPLA3 rs738409 and HCC risk in patients with HCV-related cirrhosis remains controversial. [38][39][40][41] The association between this variant and HCC risk in HCV-related cirrhosis was either marginal in our case-control study or negative in our prospective cohort. We observed the same results for TM6SF2 rs58542926 that was not associated with HCC development in casecontrol or prospective cohort of HCV-related cirrhosis.…”

Network analyses identify liver‐specific targets for treating liver diseases

“…PNPLA3 was also emphasized as a genetic determinant of risk factor for the severity of NAFLD (Salameh et al , ). Furthermore, higher prevalence for HCC development and poorer prognosis was reported to be associated with PNPLA3 polymorphism in viral and nonviral chronic liver diseases (Khlaiphuengsin et al , ). A potential unifying factor upstream of these genes is the cannabinoid‐1 receptor, stimulation of which was found to upregulate several of the above‐listed target proteins, including Fasn, Pklr, Pnpla3, and Pcsk9 in mouse models of obesity/metabolic syndrome and HCC, as documented and detailed.…”

Relationship Between Hepatic Steatosis and the Elevation of Aminotransferases in HBV-Infected Patients With HBe-Antigen Negativity and a Low Viral Load

“…Recently, several factors associated with the development of NASH (such as gene polymorphisms of the PNPLA3 gene) have been reported. 36–39 If patients with HBeAg-negativity and a low DNA level have progressive fatty liver disease due to genetic characteristic(s), then these patients could be misdiagnosed with NASH-associated cirrhosis after HBsAg seroclearance. Although Asian patients can develop NASH with a low BMI, our findings show that some of the patients who have advanced liver fibrosis with hepatic steatosis could have an HBV-related fibrotic liver after HBsAg seroclearance (observed in 1–3% of HBV-infected patients per year as described above), because HBV infection is frequently observed in Asian individuals.…”