FINAL REPORT: Identification of Genetic Determinants of the Association between Migraine and Cardiovascular Events: A Genome-Wide Association Study

Published in PLoS ONE, Volume 6, Issue 7, July 2011

Summary

Migraine increases the risk for cardiovascular disease (CVD), in particular stroke. Genetic factors contribute importantly to both migraine and CVD, however, it is unclear which genetic factors are responsible for the increased CVD risk among migraineurs. To investigate this, we compared >330,000 gene variants between migraineurs, who developed a cardiovascular event, and those who did not. Among the 5,122 women with migraine, there were 164 who developed a CVD event (heart attack, stroke, death due to CVD). No gene variant was strongly associated with any of the CVD events. However, five of the variants were suggestive to increase the risk for CVD by 3- to 12-fold. Of note, four associations appeared among migraineurs with aura and two of those with ischemic stroke. This agrees with findings that migraineurs with aura appear to have an increased risk for CVD, and this is particularly strong for ischemic stroke. But it is less clear for other CVD events like heart attack and death due to CVD. Additional studies are necessary to confirm these associations and to decipher the potential underlying biological mechanisms.

Hypothesis vs. Findings

The approach of our study, a genome-wide association study, is essentially hypothesis free, since it does not favor any gene or genetic marker over others. It was based on two kinds of previous findings: First, studies indicate a strong genetic component for both migraine and CVD. Second, migraine, in particular migraine with aura, increases the risk for CVD, especially ischemic stroke, which appears to be largely independent of classical risk factors for CVD. While we did not find gene variants that were strongly associated with CVD events among migraineurs, five variants were suggestive of an association. These appear to increase the risk for CVD by 3- to 12-fold. The findings that four of the gene variants showed an association among women with migraine with aura and two of those with ischemic stroke are in line with studies linking migraine with aura with ischemic stroke. Second, despite the large number of women with migraine (5,122) in our study, the absolute number of CVD events among migraineurs is moderate. Hence, even larger numbers of migraineurs and CVD events among them would be needed to achieve a stronger level of significance.

Unanswered Questions

We were successful in identifying gene variants with potential roles in increasing the risk for CVD among women with migraine. Two important questions remain unanswered. First, can the associations seen in our study also be found in other studies? The limitation with regard to this question is that no other population-based study with validated information on migraine and CVD events, detailed information about CVD risk factors, and genome-wide genetic information is available at present. Second, what are the biological mechanisms of these variants with respect to the migraine-CVD association?

Regarding this question, little is known about the function of the implicated genes and their mechanisms of contributing to CVD among migraineurs. Answering this will involve laboratory work including experiments with cell cultures and animal models.

What this Research Means to You

The results of our work suggest that five genes are involved in the link between migraine and cardiovascular disease, particularly stroke.  Our results will generate new hypotheses about the underlying biology as well as promote further targeted research in this area.