MTHFR C677T and A1298C Polymorphisms, Homocysteine, and Coronary Heart Disease Risk in a South Asian Adult Cohort: An Integrated Genetic-Metabolic Analysis

Background: Coronary heart disease (CHD) is a leading cause of death in South Asia. Genetic and metabolic factors play a significant role in the burden of CHD. Although associations between homocysteine, MTHFR polymorphisms, and CHD have been previously reported, the synergistic interaction of genetic variants with micronutrient deficiency and dyslipidemia in a South Asian cohort has not been adequately explored. The present study aims to elucidate these multivariate interactions to address this critical gap in knowledge. Methods: This case-control investigation was conducted among clinically confirmed CHD patients and healthy controls recruited from adults aged 35–55 years at Sri Lalithambigai Medical College & Hospital, Chennai, India, from October 2025 to January 2026. Plasma homocysteine, folate, vitamin B12, and lipid profiles were determined using chemiluminescent and enzymatic assays. Genotyping of MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms was performed using PCR-RFLP analysis. Statistical analyses included Pearson correlation, multivariate logistic regression with interaction analysis, ROC curve analysis, and a composite risk scoring model. Results: Plasma homocysteine levels were significantly elevated in CHD patients (37.69±2.86 µmol/L) compared to controls (18.41±4.02 µmol/L; p<0.001). Folate levels were significantly lower in CHD patients (8.37±4.24 ng/mL) versus controls (10.03±8.67 ng/mL; p<0.001). Both groups demonstrated vitamin B12 values below the conventional reference range (200–900 pg/mL), consistent with the high prevalence of B12 insufficiency in South Indian vegetarian-predominant populations; notably, CHD patients showed comparatively higher B12 levels (105.37±12.58 pg/mL vs. 80.32±15.67 pg/mL in controls; p<0.001), the interpretation of which is discussed. Risk genotypes for MTHFR C677T (CT+TT) and A1298C (AC+CC) were significantly more prevalent in CHD patients, with odds ratios of 2.4 (95% CI: 1.13–3.80) and 2.92 (95% CI: 1.34–10.44), respectively. The composite genetic-metabolic risk score achieved an AUC of 0.912, outperforming individual biomarkers. Conclusions: Integrated evaluation of MTHFR polymorphisms, hyperhomocysteinemia, micronutrient deficiencies, and dyslipidemia shows promise for improving CHD risk stratification in South Asian populations. These findings are associative in nature and require prospective cohort validation before informing clinical application. Population-specific, genotype-guided nutritional intervention strategies warrant further investigation through randomised controlled trials.