The Relationship Between Homocysteine and Genes of Folate‐Related Enzymes in Migraine Patients

(Headache 2010;50:99-168) Background.— It has been suggested that homocysteine (Hcy) and the 5′-10′-methylenetetrahydrofolate reductase (MTHFR) C677T variant are implicated in the pathogenesis of migraine. Homocysteine has the potential to damage endothelium and accelerate atherosclerosis. Genetic factors such as the MTHFR C677T polymorphism, and other polymorphisms in folate-related genes associated with high homocysteine levels, may contribute to increasing this vascular risk. Results.— We recruited 427 migraine patients (199 without aura [MO]; 228 with aura [MA]), and 310 controls in a neurologic clinic. Hcy levels and 6 polymorphisms corresponding to 6 folate-related genes, including the MTHFR C677T variant, were determined in all migraine participants and in a subset of 155 controls. We found higher sex-adjusted Hcy levels in MA (mean: 11.02 µM) than MO patients (9.86 µM; P = .005 for the difference). Hcy levels higher than 12.0 µM doubled the risk for MA (OR = 2.145; 95% confidence intervals [CI] = 1.3-3.4; P = .001), and those higher than 15.0 µM incurred a 6-fold increase (OR = 5.95; 95% CI = 2.1-20.0, P < .001). The number of MTHFR 677T alleles was the best genetic predictor of Hcy levels (r2 = 0.06; P = 6.2e-6; corrected for genetic variants analyzed) and this effect remained significant after correction for other confounding factors. Using multi-dimensionality reduction approaches, we observed significant epigenetic interaction among some of the folate-related genetic variants to predict higher Hcy levels, and also among higher Hcy levels and folate-related genetic variants to predict the end-diagnosis of MA only among migraineurs. In controls, Hcy levels and the number of MTHFR 677T alleles were found to be intermediate between those observed in MA and MO patients. Conclusion.— Our results suggest that MA patients have higher Hcy levels. We also observed complex epigenetic interaction among folate-related enzymes, sex, and Hcy levels predicting MA phenotype. Nevertheless, genetic factors explained only a minor proportion of the variance for both Hcy plasma levels and for predicting MA phenotype. Determination of MTHFR C677T polymorphisms and Hcy levels may be useful to identify patients with a high risk of suffering from MA.