A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression.

Many homeostatic genes are thought to play a role in the susceptibility to migraine, making it a highly complex neurovascular disease. In this meta-analysis, our primary objective was to evaluate whether or not MTHFR variants (such as C677T and A1289C) and ACE I/D were associated with an increased risk of migraine. Using a PRISMA-based systematic literature-review guideline, internet sources such as PubMed and Google Scholar were searched to identify the genes of interest and migraine risk. To pool the data, odds ratios with 95% confidence intervals were calculated utilizing different genetic models. Cochran's Q Test and I 2 statistics were used to access heterogeneity, while Begg's and Egger's tests were used to identify publication bias. All tests were two-sided, and a p-value of < 0.05 was regarded as statistically significant. The present meta-analysis observed that the C677T variant is significantly associated with the increased risk of migraine (allele model: OR:1.19, CI [1.07-1.33], I 2  = 78%) and its clinical subtype i.e., MA (allele model: OR: 1.26, CI [1.09-1.45], I 2  = 80%) in the overall population. Concerning the ACE- I/D, it significantly increased the risk of overall migraine and both clinical subtypes after utilizing the dominant genetic models (OR: 1.14, CI [1.01-1.29], I 2 % = 32). Concerning the MTHFR A1289C, only the codominant model (HR vs HT) and recessive model significantly increased the risk of overall migraine. Therefore, the findings of the present meta-analysis showed that MTHFR-C677T is an important risk factor for migraine and its clinical subtype.