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In a recent meta-analysis migraine was associated with a two-fold increase in stroke risk. While the mechanism driving this association is unknown, one intriguing hypothesis is that migraineurs are genetically predisposed to developing ischemic stroke. Mutations in the  ATP1A2  gene are implicated in familial hemiplegic migraine type II and increase the severity of ischemic brain injury in animal models. To further explore these observations, we assessed the association between  ATP1A2  polymorphisms, migraine, and the risk of ischemic stroke in participants of the Genetics of Early-Onset Stroke Study, a population-based case–control study of ischemic stroke among men and women aged 15–49. Using responses to a headache symptoms questionnaire, subjects were classified as having no migraine, or migraine with or without visual aura. Evaluating a total of 134  ATP1A2  polymorphisms genotyped using a combination of Illumina platforms (Cardiovascular Gene-centric 50 K SNP Array and HumanOmni1-Quad_v1-0_B Bead Chip), only one polymorphism ( rs2070704 ) demonstrated a nominally significant association with stroke in an age-, gender-, ethnicity-adjusted model (OR = 0.83, 95% CI = 0.71-0.98, p = 0.025) and in a vascular risk factor model adjusting for age, gender, ethnicity, hypertension, diabetes, smoking, and myocardial infarction (OR = 0.74, 95% CI = 0.63-0.89, p = 0.001). Ethnicity-stratified analyses demonstrated a significant association for  rs2070704  among African-Americans (OR = 0.68, 95% CI = 0.53-0.90, p = 0.005) but not Caucasians (OR = 0.82, 95% CI = 0.64-1.04, p = 0.107). These associations were unchanged when migraine subtypes were included as co-variates. We did not observe an association between  ATP1A2  polymorphisms and migraine. While our results do not demonstrate a strong relationship between  ATP1A2  polymorphisms and migraine associated stroke risk, the results are hypothesis generating and indicate that an association between  ATP1A2  polymorphisms and stroke risk may exist. Additional studies are required.   Electronic supplementary material  The online version of this article (doi:10.1186/2193-1801-2-46) contains supplementary material, which is available to authorized users.

Polymorphisms in migraine-associated gene, atp1a2, and ischemic stroke risk in a biracial population: the genetics of early onset stroke study