Association between single nucleotide polymorphisms in PNPLA3, TM6SF2 and MBOAT7 genes and markers of cancer aggressiveness in a Sri Lankan NASH-related HCC cohort.

Background: Single nucleotide polymorphisms (SNPs) 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 were reported to be strongly associated with non-alcoholic fatty liver disease (NAFLD) pathogenicity among different populations. We investigated whether these SNPs are associated with prognostic factors and genetic biomarkers of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) in the Sri Lankan context.

Methods: We conducted an exploratory study to evaluate the prevalence of five SNPs (PNPLA3 rs738409, PNPLA3 rs2281135, PNPLA3 rs2294918, TM6SF2 rs58542926 and MBOAT7 rs641738) as genetic risk factors for NASH-HCC pathogenicity. We genotyped 48 NASH-HCC patient samples collected at a clinical setting using a minisequencing method. Impact of each SNP with tumor prognostic factors such as nodularity, tumor size and AFP (alpha-feto protein) level was analyzed using chi square test. We also analyzed the expression of micro RNA-122 (miR-122) in serum and leukocyte telomere length via quantitative real-time PCR. Associations between each SNP with micro RNA-122 (miR-122) expression level and leukocyte telomere length of NASH-HCC patients were analyzed using one-way analysis of variance (ANOVA) test and independent t test. Relationships among tested SNPs and some well-established HCC risk factors such as age, BMI, gender, diabetes status and the cirrhotic stage were also analyzed using chi square test, independent t-test and One-way ANOVA test.

Results: Our analyses demonstrated significant associations between PNPLA3 rs2281135 variant and tumor nodularity. Also, PNPLA3 rs2281135 and PNPLA3 rs2294918 variants were significantly associated with miR-122 expression levels of NASH-HCC patients. Further, age and body mass index (BMI) were significantly associated with PNPLA3 rs2281135 variant in our study cohort.

Conclusion: We found that in the Sri Lankan NASH-related HCC cohort, some PNPLA3 variants (rs2281135 and rs2294918) correlate with tumor nodularity, higher miR-122 expression, and distinct demographic features such as age and BMI. Our work highlights the role of specific SNPs in tumor aggressiveness, contributing to the precision screening for HCC in NASH patients.