Genetics and epigenetics in tumor necrosis factor-alpha (TNF-α) and transmembrane 6 superfamily member 2 (TM6SF2) in alcohol induced liver cirrhosis
Background Alcohol dependence and cirrhosis are key outcomes of increased alcohol use, with genetic factors increasingly implicated. A functional promoter variant (rs361525) in the TNF-α gene may contribute to ALD pathogenesis, while a loss-of-function variant (rs58542926) in TM6SF2 modifies liver disease progression. We aimed to study these SNPs and assess DNA methylation at TM6SF2 loci in individuals with and without alcohol-related cirrhosis. Methods The study included men (N = 243) with alcohol dependence with cirrhosis (AUD-C+ve) and without cirrhosis (AUD-C-ve), based on ICD-10 criteria, recruited from SJMCH. Fibroscan and/or sonography (LSM < 14 kPa) ruled out severe fibrosis. Genotyping was performed for TNFα (rs361525) and TM6SF2 (rs58542926). Genomic DNA (N = 100) underwent bisulfite conversion followed by pyrosequencing at TM6SF2 loci. Methylation levels were calculated separately for individual CpG sites and as the mean of four CpG sites. Group differences were assessed using unpaired t-tests, and genetic models were applied based on risk allele status. Results Genotype and allele frequencies at both loci were comparable between AUD-C+ve and AUD-C–ve groups. TM6SF2 methylation was significantly reduced in the AUD-C+ve group (uncorrected p = 0.03). A trend was also noted for TNF-genotype with A-carriers having lower TM6SF2 global methylation levels (p = 0.06). We did not observe any differences in genotype and allele frequencies for both TM6SF2 and TNFα variants. Duration of alcohol consumption was significantly associated with TM6SF2 methylation (p = 0.02). Conclusion TM6SF2 hypomethylation in AUD-C+ve individuals may influence lipid metabolism and contribute to liver injury and HCC progression. Reduced methylation among TNF-α risk allele carriers suggests a potential gene–epigenetic interaction. Overall, higher alcohol exposure and genetic susceptibility may together predispose to worsening alcohol-related cirrhosis.