APOORVA SINGH AND RAJESH SHARMA
Abstract
Folate-mediated one-carbon metabolism (OCM) supports nucleotide synthesis and methylation. Perturbations of OCM are linked to hyperhomocysteinemia and genomic instability, and functional polymorphisms in MTHFR (C677T) and MTR (A2756G) may modify susceptibility under exposures such as alcohol consumption and tobacco use. To estimate genotype/allele frequencies of MTHFR C677T and MTR A2756G and evaluate their association with alcohol/tobacco user status in a pilot cohort from Eastern Uttar Pradesh (UP), India. We constructed a pilot caseâcontrol subset (N = 200; 100 alcohol/tobacco users and 100 controls) from an institutional dataset with PCRâRFLP genotype calls. For MTHFR C677T, genotypes were coded as CC/CT/TT; for MTR A2756G, genotypes were coded as AA/AG/GG. We compared genotype distributions using a 2Ã3 chi-square test, assessed Hardyâ Weinberg equilibrium (HWE) in controls, and estimated odds ratios (OR) under a dominant model (variant carriers vs. non-carriers) using Fisherâs exact test and age/sex-adjusted logistic regression. Control genotypes satisfied HWE for both variants (MTHFR: p = 0.170; MTR: p = 0.140). MTHFR C677T showed no evidence of association with case status (genotype p= 0.538; dominant OR 1.16 [95% CI 0.62â2.16], p = 0.752). In contrast, MTR A2756G differed between groups (genotype p = 0.031), with a higher G-allele frequency in cases (21.5%) versus controls (12.0%). Under a dominant model (AG/GG vs. AA), MTR variant carriers had increased odds of being cases (unadjusted OR 2.31 [95% CI 1.23â4.32], p = 0.013; adjusted OR 2.34 [95% CI 1.18â4.61], p = 0.015). In this pilot Eastern UP cohort, MTR A2756G (but not MTHFR C677T) showed an association with alcohol/tobacco use. Larger, exposure-stratified analyses with balanced covariates and nutritional biomarkers (folate, vitamin B12, homocysteine) are warranted to clarify geneâenvironment effects.