Migraine Susceptibility: Role for Vascular and Hormonal Gene Variants

Abstract

Migraine is a multifactorial disorder characterised by headpain, nausea, vomiting, photophobia and often severe, neurological disturbances. Neurotransmitter-related pathways have been the main focus of studies investigating the molecular mechanisms of the disorder. However vascular and hormonal disturbances also occur in migraineurs, as highlighted by alterations in cerebral blood flow and hormonal triggers of migraine, particularly in women. We have recently investigated a number of genetic factors involved in these functions. These studies have provided evidence implicating variants in the methylenetetrahydrofolate reductase (MTHFR) and angiotensin I-converting enzyme (ACE) genes, as interacting determinants of migraine. Specifically, our results indicated that MTHFR acts synergistically with ACE to increase total migraine risk by ~2-fold and migraine with aura-specific risk by ~3 fold.We have also investigated a number of hormonal gene variants. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. A recent study in our laboratory examined estrogen receptor and progesterone receptor genes for a potential role in migraine. Results of the ESR1 analysis showed a significant difference between 224 unrelated migraineurs compared to 224 controls in both allele frequencies (P=0.003) and genotype frequencies (P=0.008). An independent follow-up case/control study of 520 individuals also resulted in a significant association with regard to allele frequencies (P=8x10-6) and genotype frequencies (P=4x10-5). Results of the progesterone receptor analysis also showed significant results, both in the first study group, (allele frequencies P=0.02, and genotype frequencies P=0.04), and in the independent follow-up group (allele frequencies P=0.003, and genotype frequencies P=0.02). Furthermore, interaction analysis revealed that individuals who carried at least one copy of both susceptibility genotypes were 3.2 times more likely to suffer from migraine, indicating that these genes appear to act synergistically to increase the risk of migraine.