Association of MTHFR C677T Polymorphism with Risk of Lacunar InfarctionGenetic variation linked to increased risk of lacunar infarction

BACKGROUND: The association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and lacunar infarction (LI) remains inconclusive. METHODS: The literature retrieval encompassed PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang (inception - March 2026). Case-control studies that reported genotype frequencies of MTHFR C677T (CC, CT, and TT) in LI patients and controls were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for 5 genetic models were calculated using random/fixed-effects models in Stata 13.0. Prespecified exploratory subgroup analyses were conducted by ethnicity and symptom status. Four methodological sensitivity analyses assessed the robustness of findings by restricting analyses to studies with magnetic resonance imaging (MRI) only versus CT/MRI, Trial of Org 10172 in Acute Stroke Treatment classification versus radiological criteria, Hardy-Weinberg equilibrium-compliant controls, and Newcastle-Ottawa Scale score ≥ 7. Meta‑regression, heterogeneity (I2), and publication bias (Begg/Egger tests with trim‑and‑fill) were also performed. RESULTS: Twelve studies comprising 5097 participants (1598 cases/3499 controls) were included. Significant associations were observed in 4 genetic models: recessive (TT vs CT + CC): OR = 1.36, 95% CI = 1.05 to 1.77; dominant (TT + CT vs CC): OR = 1.22, 95% CI = 1.05 to 1.41; allelic model (T vs C): OR = 1.19, 95% CI = 1.07 to 1.33; and homozygous contrast (TT vs CC): OR = 1.45, 95% CI = 1.11 to 1.89. Exploratory subgroup analyses, limited by small numbers of studies in several strata, suggested stronger associations in Asian populations and symptomatic lacunar stroke; these findings are underpowered and should be interpreted with caution. Sensitivity analyses restricting to MRI‑only studies, Trial of Org 10172 in Acute Stroke Treatment‑defined cases, Hardy-Weinberg equilibrium‑compliant controls, or higher‑quality studies (Newcastle-Ottawa Scale ≥ 7) produced results broadly consistent with the primary findings. However, significant publication bias was detected, and all pooled ORs decreased and lost statistical significance after trim‑and‑fill adjustment. CONCLUSION: The initially observed association between MTHFR C677T and LI was no longer significant after trim‑and‑fill adjustment for publication bias. All analyses used unadjusted crude genotype data, so residual confounding by vascular and nutritional factors cannot be excluded, and the pooled estimate combined distinct lacunar phenotypes. A formal assessment using the Grading of Recommendations Assessment, Development and Evaluation framework showed very low certainty of evidence. Routine MTHFR genotyping for LI risk assessment is therefore not currently supported, and further rigorous studies are warranted.