Association of MTHFR C677T polymorphism with risk of atherosclerotic cardiovascular diseases: a systematic review and meta-analysis

Although several meta-analyses have examined the association between MTHFR C677T and specific cardiovascular outcomes, a comprehensive evaluation focusing on atherosclerotic cardiovascular disease (ASCVD) as a unified outcome, incorporating recently published studies (January 2016–March 2026), remains limited. Potential studies were selected from Embase, Web of Science, and PubMed databases. Pooled effect size was evaluated by odds ratios (ORs) with 95% confidence intervals (CIs) using random-effects models where significant heterogeneity was present. Twenty-three case-control studies (including 6693 patients and 7692 controls) from January 2016 to March 2026 were enrolled in this study. Significant heterogeneity was observed across models (I² > 50%, all p het < 0.001), and random-effects models were applied. MTHFR C677T was positively correlated to ASCVD risk under the dominant model (OR = 1.71, 95%CI = 1.35–2.16), the recessive model (OR = 1.73, 95%CI = 1.35–2.23), and the allelic model (OR = 1.55, 95%CI = 1.30–1.84). Supplementary genotype-specific comparisons also showed significant associations. Subgroup analysis identified a significant correlation in studies of East Asian and North African populations, younger individuals, and healthy controls. The association was significant in coronary artery disease (CAD) and ischemic stroke (IS) patients. Region, age, control type, and disease type are the sources of heterogeneity. MTHFR C677T was positively correlated with ASCVD risk across multiple genetic models.