Abstract
BackgroundThe C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Migraine, with and without aura (MA and MO), is a prevalent and complex neurovascular disorder that may also be affected by genetically influenced hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene is associated with migraine susceptibility we utilised unrelated and family-based case-control study designs.MethodsA total of 652 Caucasian migraine cases were investigated in this study. The MTHFR C677T variant was genotyped in 270 unrelated migraine cases and 270 controls as well as 382 affected subjects from 92 multiplex pedigrees.ResultsIn the unrelated case-control sample we observed an over-representation of the 677T allele in migraine patients compared to controls, specifically for the MA subtype (40% vs. 33%) (χ2 = 5.70, P = 0.017). The Armitage test for trend indicated a significant dosage effect of the risk allele (T) for MA (χ2 = 5.72, P = 0.017). This linear trend was also present in the independent family-based sample (χ2 = 4.25, Padjusted = 0.039). Overall, our results indicate that the T/T genotype confers a modest, yet significant, increase in risk for the MA subtype (odds ratio: 2.0 – 2.5). No increased risk for the MO subtype was observed (P > 0.05).ConclusionsIn Caucasians, the C677T variant in the MTHFR gene influences susceptibility to MA, but not MO. Investigation into the enzyme activity of MTHFR and the role of homocysteine in the pathophysiology of migraine is warranted.
Highlights
The C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease
The International Headache Society (IHS) has defined two major classes of migraine. These are migraine without aura (MO), which accounts for ~70% of all migraine in the population, and migraine with aura (MA), which comprises ~25% of all migraine [1]
Unrelated case-control analysis Table 1 displays the frequency distributions observed for the MTHFR C677T variant for the unrelated case and control groups
Summary
The C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. With and without aura (MA and MO), is a prevalent and complex neurovascular disorder that may be affected by genetically influenced hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene is associated with migraine susceptibility we utilised unrelated and family-based case-control study designs. Migraine is a debilitating neurovascular disease that affects approximately 12% of the Caucasian population. It is characterised by nausea and vomiting, photophobia and phonophobia, neurological disturbances and severe recurrent headache. The IHS has defined two major classes of migraine. These are migraine without aura (MO), which accounts for ~70% of all migraine in the population, and migraine with aura (MA), which comprises ~25% of all migraine [1]. The two subtypes have substantial symptomatic overlap, but MA sufferers experience distinguishing neurological disturbances (the aura) that usually precede the headache phase of an attack [1]
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