What is the association between the MTHFR C677T polymorphism and migraine susceptibility among populations in the Middle East? A systematic review

Abstract Background Migraine is a common multifactorial neurovascular disorder with a substantial genetic component. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been implicated in migraine susceptibility, particularly migraine with aura, through its effects on folate metabolism and homocysteine regulation. However, findings remain inconsistent across populations, and evidence from the Middle East is limited. Objective To systematically evaluate the association between the MTHFR C677T polymorphism and migraine susceptibility among populations from countries represented in the eligible evidence (Turkey, Iran, Egypt). Methods A systematic review was conducted in accordance with PRISMA 2020 guidelines and prospectively registered in PROSPERO (CRD420251164175). Electronic databases (PubMed, PMC, and DOAJ) were searched up to October 9, 2025. Eligible studies included case–control investigations assessing MTHFR C677T polymorphism in migraine patients and controls from countries represented in the eligible evidence (Turkey, Iran, Egypt). Findings were synthesized narratively due to heterogeneity in study design, populations, and outcome reporting. Study quality was assessed using the Newcastle–Ottawa Scale. Results Six case–control studies comprising 793 migraine patients and 848 controls met the inclusion criteria. Most included studies reported a significant association between the MTHFR C677T polymorphism and increased migraine susceptibility, particularly among individuals carrying the TT genotype. The association was more consistently observed in migraine with aura compared to migraine without aura, although several studies also reported a relationship with migraine without aura. One study did not find a significant overall association. Evidence regarding other MTHFR variants, including A1298C and rs4846049, was limited and inconsistent across studies. Conclusion This systematic review suggests a consistent association between the MTHFR C677T polymorphism, particularly the TT genotype, and migraine susceptibility in populations from countries represented in the eligible evidence (Turkey, Iran, Egypt). Several included studies indicate a stronger relationship with migraine with aura, supporting the potential involvement of MTHFR-related metabolic pathways in migraine pathophysiology. The observed patterns highlight the possible influence of regional genetic and environmental factors; however, the absence of quantitative synthesis limits the ability to estimate pooled effect sizes.