The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups

Abstract

Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis, hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRα) gene for a potential role in migraine pathogenesis and susceptibility A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P = 0.003) and genotype distributions (P = 0.008) in this sample.An independent follow-up study was then undertaken using this marker in an additional population based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P = 8x10 -6 ) and genotype distributions (P = 4x10 -5 ).Our findings support the hypothesis that genetic variation in hormone receptors, in particular the estrogen receptor 1 gene, may play a role in migraine.

Current and prospective pharmacological targets in relation to antimigraine action

“…Similarly, individuals carrying the PROGINS inserts of the progesterone receptor gene polymorphism are twice as likely to suffer from migraine than control subjects (Colson et al 2005). It is worth mentioning that the estrogen receptor polymorphism increases its expression (Colson et al 2004), whereas the progesterone receptor polymorphism negatively impacts its expression. Furthermore, it is interesting that the PROGINS allele of the progesterone receptor acts synergistically with the 594A allele of ESR1 to increase the risk of migraine by 3.2 times (Colson et al 2005).…”

“…Primary evidence for the involvement of female sex hormones in migraine pathogenesis comes from the facts that the prevalence of migraine is 2-3-fold higher in women than in men (Lipton et al 2001;Stewart et al 1992) and that reproductive milestones such as menarche, pregnancy, and menopause are associated with changes in migraine frequency and/or severity (Silberstein 2000). Interestingly, individuals with a polymorphism at G594 (exon 8) of the estrogen receptor-1 (ESR1) gene are twice more likely to suffer from migraine than those with the wild-type gene (Colson et al 2004). Similarly, individuals carrying the PROGINS inserts of the progesterone receptor gene polymorphism are twice as likely to suffer from migraine than control subjects (Colson et al 2005).…”

Vascular Actions of Estrogens: Functional Implications

“…Several genetic polymorphisms are associated with familial migraine including genetic variation in ER␣ (G594A polymorphism of exon 8) (Colson et al, 2004(Colson et al, , 2006Johnson et al, 2007). As discussed above (section V.C), estrogen receptors are located within brain nuclei that innervate the cerebral vasculature as well as other nuclei regulating cardiovascular function (Martin and Behbehani, 2006).…”

Genetics of Migraine - Is There any Progress?

“…However, the results of studies of genetic association are controversial, although there are some positive results [86][87][88][89][90][91][92][93]. In a recent study, three estrogen receptor 1 (ESR1) haplotypes were associated with the disease.…”