Association and impact of SNPs in PNPLA3, TM6SF2 and MBOAT7 genes on prognosis factors of hepatocellular carcinoma with non-viral etiology

Abstract

Background: Hepatocellular carcinoma (HCC) is becoming a challenging global health concern with Asian and African countries carrying the highest burden of it. The rising prevalence of non-alcoholic steatohepatitis (NASH) associated HCC is linked with unhealthy dietary patterns and sedentary life styles. In addition, genetic predisposition may play a critical role in developing NASH-related HCC. Previous studies have identified that variants in patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are significantly associated with non-alcoholic fatty liver disease (NAFLD) pathogenicity among different populations. But there are no published reports on their impact on Sri Lankan NASH-HCC patients. Methods: We conducted an exploratory study to evaluate the prevalence of five single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, PNPLA3rs2281135, PNPLA3 rs2294918, TM6SF2 rs58542926 and MBOAT7 rs641738) as genetic risk factors for NASH-HCC pathogenicity. We genotyped 48 NASH-HCC samples that were collected at a clinical setting and analyzed using statistical modelling to explore the impact of each SNP with tumor prognostic factors. Results: We observed high frequencies in four out of five polymorphisms, namely PNPLA3 rs738409 (0.79, 95%CI 0.650-0.895), PNPLA3 rs2281135 (0.77, 95%CI 0.627-0.880), PNPLA3 rs2294918 (0.9, 95%CI 0.773-0.965) and MBOAT7rs641738 (0.85, 95%CI 0.722-0.939) among Sri Lankan NASH-HCC patients. Our analyses further demonstrated significant associations of PNPLA3variants with a total tumor diameter of NASH-HCC patients while PNPLA3 rs2294918 and MBOAT7 rs641738 had significant associations with single-nodular HCC. Of the five SNPs, we observed a strong correlation between PNPLA3 rs738409 and PNPLA3 rs2294918 through pairwise linkage disequilibrium (LD) analysis. Conclusion: Observed high frequencies of risk alleles among genotyped SNPs warrants the possibility of genetic predisposition as a risk factor for NASH-related HCC in the Sri Lankan setting.