DNA Methylation change in genes involved in Alcohol metabolism (ALDH2) and One-carbon metabolism (MTHFR) pathways among people with Alcohol Use Disorder

Background: Alcohol Use Disorder (AUD) is a significant public health issue influenced by genetic and environmental factors. Genetic loci linked to age of initiation, response to alcohol, and withdrawal complications.Alcohol inhibits methionine synthase (MS), disrupting the conversion of homocysteine to methionine and altering levels of S-adenosyl methionine (SAM) and S-adenosylhomocysteine (SAH), which are regulated by DNA methyltransferases (DNMTs). MTHFR, a key enzyme in one-carbon metabolism, and ALDH2, involved in alcohol metabolism, are associated with AUD.Single nucleotide variants in MTHFR are associated with alcohol withdrawal seizures. Hyperhomocysteinemia has been noted in alcohol-dependent individuals with seizures and brain atrophy. Emerging evidence suggests epigenetic mechanisms may underlie such outcomes.Methods: The study included 108 male AUD patients (ICD-10 criteria) from St. John’s Medical College Hospital and NIMHANS. Of these, 19 had seizures (SZ + ve), and 89 did not (SZ − ve). Genotyping for ALDH2 (rs2238151) and MTHFR (rs1801133, rs1801131) was done. Plasma homocysteine levels were estimated. DNA was bisulfite converted, and methylation at MTHFR and ALDH2 loci was assessed by pyrosequencing. Statistical tests were carried out to evaluate the resultsResults: Significant hypomethylation at 3 CpG sites in MTHFR was seen in SZ + ve vs. SZ − ve (p < 0.01), even after adjusting for alcohol intake. Decreased methylation at ALDH2 loci was noted but not statistically significant.Conclusion: Changes in methylation levels of MTHFR may perturb this pathway, and thus affect brain function. Altered methylation in blood DNA at candidate loci might serve as a biomarker for prolonged severe alcohol abuse.