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Interrelationships among the MTHFR 677C>T polymorphism, migraine, and cardiovascular disease

From the Division of Preventive Medicine (M.S., R.Y.L.Z., J.E.B., T.K.) and Division of Aging (J.E.B., T.K.), Department of Medicine, Brigham and Women's Hospital, and Department of Ambulatory Care and Prevention (J.E.B.), Harvard Medical School; and Department of Epidemiology (J.E.B., T.K.), Harvard School of Public Health, Boston, MA.

Address correspondence to Dr. Tobias Kurth, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, 3rd Fl, Boston, MA 02215-1204 tkurth{at}rics.bwh.harvard.edu.

Background: Interrelationships among the MTHFR 677C>T polymorphism (rs1801133), migraine, and cardiovascular disease (CVD) are plausible but remain controversial.

Methods: Association study among 25,001 white US women, participating in the Women's Health Study, with information on MTHFR 677C>T polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationships of genotype and migraine on incident CVD.

Results: At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During a mean of 11.9 years of follow-up, 625 CVD events occurred. Carriers of the TT genotype were less likely to have migraine with aura. The multivariable-adjusted relative risk (RR) in the recessive model was 0.79 (95% CI = 0.65–0.96; p = 0.02). The TT genotype did not increase the risk for CVD. In contrast, migraine with aura doubled the risk for CVD (multivariable-adjusted RR = 2.06; 95% CI = 1.53–2.78; p < 0.0001). Coexistence of migraine with aura and the TT genotype selectively raised this risk (RR = 3.66; 95% CI = 1.69–7.90; p = 0.001). This pattern was driven by a fourfold increased risk for ischemic stroke (multivariable-adjusted RR = 4.19; 95% CI = 1.38–12.74; p = 0.01) and was not apparent for myocardial infarction.

Conclusions: Data from this large cohort of women suggest a modest protective effect of the MTHFR 677TT genotype on migraine with aura. The increased risk for cardiovascular disease among migraineurs with aura was magnified for TT genotype carriers, which was driven by a substantially increased risk of ischemic stroke.

Abbreviations: CVD = cardiovascular disease; HR = hazard ratio; IHS = International Headache Society; MI = myocardial infarction; OR = odds ratio; RR = relative risk; WHS = Women's Health Study.

Supplemental data at www.neurology.org.

e-Pub ahead of print on July 30, 2008, at www.neurology.org.

*These authors contributed equally to the work.

The Women's Health Study is supported by grants from the National Heart, Lung, and Blood Institute (HL-43851 and HL-080467) and the National Cancer Institute (CA-47988). Research for this work was supported by grants from the Donald W. Reynolds Foundation, the Leducq Foundation, and the Doris Duke Charitable Foundation. F. Hoffmann La-Roche and Roche Molecular Systems, Inc., supported the genotype determination financially and with in-kind contribution of reagents and consumables. Dr. Schürks was supported by a grant from the Deutsche Forschungsgemeinschaft (SCHU 1553/2-1). The funding agencies played no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Disclosure: Author disclosures are provided at the end of the article.

Received October 23, 2007. Accepted in final form March 20, 2008.

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