MTHFR C677T and A1298C polymorphisms and their association with ischemic stroke in populations from five Middle Eastern countries: a systematic review and meta-analysis

Abstract

Abstract Background Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have been investigated in relation to ischemic stroke, but findings vary across populations and genetic models. Evidence from Middle Eastern countries remains geographically limited and should not be interpreted as representing a homogeneous genetic population. Objective To systematically evaluate the association of MTHFR C677T and A1298C polymorphisms with ischemic stroke in populations from Middle Eastern countries represented in the available evidence. Methods PubMed/MEDLINE, Scopus, and Web of Science Core Collection were searched from inception through October 2, 2026. Eligible studies were original human observational genetic-association studies reporting MTHFR C677T and/or A1298C data in ischemic stroke or cerebral infarction cases and controls. Primary quantitative analyses were restricted to adult datasets with directly extractable genotype or allele counts. Random-effects odds ratios (ORs) were pooled using inverse-variance weighting with restricted maximum-likelihood estimation of between-study variance. Allele, dominant, recessive, homozygous, and heterozygous contrasts were evaluated as correlated genetic models. Heterogeneity was assessed using I² and τ², and 95% prediction intervals were calculated. Hartung–Knapp confidence intervals and Hardy–Weinberg equilibrium-restricted, leave-one-out, sparse-data, and study-specific sensitivity analyses were performed. Pediatric evidence was analyzed separately as secondary evidence. Results Seventeen reports from Turkey, Iran, Egypt, Iraq, and Saudi Arabia were included in the qualitative synthesis. Nine independent adult datasets contributed to the primary C677T analysis (916 cases and 1396 controls), and six contributed to the A1298C analysis (862 cases and 1121 controls). For C677T, conventional random-effects confidence intervals were above the null for the allele (OR 1.49, 95% CI 1.18–1.87), dominant (1.69, 1.08–2.64), recessive (1.76, 1.27–2.43), and homozygous (2.35, 1.41–3.92) contrasts, whereas the heterozygous comparison was imprecise (1.58, 0.99–2.53). Hartung–Knapp confidence intervals remained above the null only for the allele, recessive, and homozygous C677T contrasts. For A1298C, conventional random-effects confidence intervals were above the null for the allele, dominant, recessive, and homozygous contrasts, whereas Hartung–Knapp intervals remained above the null only for the allele and homozygous comparisons. Substantial heterogeneity and wide prediction intervals limited the generalizability of several model-specific estimates. Conclusion The available adult evidence suggests model-dependent associations between MTHFR C677T and A1298C polymorphisms and ischemic stroke in the represented populations. For C677T, the allele, recessive, and homozygous comparisons showed comparatively greater consistency across conventional random-effects and Hartung–Knapp analyses. For A1298C, the allele and homozygous comparisons showed comparatively more consistent statistical evidence. However, the limited number of datasets, heterogeneity, potential population stratification, and study-level methodological limitations warrant cautious interpretation. These unadjusted associations do not establish causality or clinical predictive utility.