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

Abstract

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 materialThe online version of this article (doi:10.1186/2193-1801-2-46) contains supplementary material, which is available to authorized users.

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“…These results are compatible to findings in other studies (Reeves et al, 2010) (Harriott et al, 2013).…”

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“…Only 4 candidate gene studies met our PubMed search criteria examining the genetic associations with IS risk among cases ≤50-year old (Table 3). 58–61 The MTHFR C677T variant (rs1801133), a missense variant encoding A222V amino acid change, was reported to be significantly associated with early-onset IS in the meta-analysis of 8 studies with a total of 1093 cases (OR=1.44; P =0.002; Xin et al 58 ). The same study also reported significant associations with APOE (rs7412 and rs429358; OR=2.53; P <0.001) and ITGA2 C807T (rs1126643; OR=1.50; P =0.01), although they also detected evidence for potential publication bias for this latter result, calling the ITGA2 association into question.…”

“…59 Consistent with this meta-analysis, the largest single study of unselected early-onset IS cases found no association between FVL and IS (OR=1.0). 60 Harriott et al 61 studied the relationship between 134 polymorphisms of ATP1A2 , a migraine-associated gene, with early-onset IS and only 1 variant reached nominal significance (rs2070704), suggesting no strong association between the ATP1A2 and early-onset IS.…”

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