The influence of genetic constitution on migraine drug responses.
OBJECTIVE
Specific acute treatments of migraine are 5HT1B/D receptor agonists; triptans and ergotamine, but only two-thirds of patients respond well without side effects. No migraine-prophylactic drugs are specific to migraine. Prophylactic drugs are selected by time-consuming "trial and error." Personalized treatment is therefore much needed. The objective of this study was to test the effect of 12 single nucleotide polymorphisms (SNPs) significantly associated with migraine on migraine drug responses.


METHODS
Semi-structured migraine interviews including questions on drug responses, blood samples and genotyping were performed on 1806 unrelated migraine cases recruited from the Danish Headache Center. Association analyses were carried out using logistic regression, assuming an additive model for the genetic effect. The effect on drug responses was tested for a combined genetic score and for each of the 12 SNPs. Significant findings were subsequently tested in an independent replication sample of 392 unrelated Danish migraine cases.


RESULTS
A single risk variant, rs2651899 in PRDM16, was significantly associated with efficacy of triptans with an odds ratio (OR) of treatment success of 1.3, and a higher combined genetic score was significantly associated with efficacy of triptans with an OR of success of up to 2.6. A number of SNPs showed nominal preferential association with the efficacy of triptans and others with prophylactic drugs. Analyses of triptans and ergotamine complemented each other and gave a stronger signal when analyzed together. The associations between response to triptans and genetic load and rs2651899 were partially confirmed in the independent sample.


CONCLUSIONS
We show for the first time an association between genetic constitution and migraine drug response. This is a first step toward future individualized medicine.
Danish Headache Center, Department of Neurology, Faculty of Health and Medical Sciences, Glostrup Hospital, University of Copenhagen, Denmark.
Anne Francke
AF
Christensen
Danish Headache Center, Department of Neurology, Faculty of Health and Medical Sciences, Glostrup Hospital, University of Copenhagen, Denmark.
Ann-Louise
AL
Esserlind
Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark.
Thomas
T
Werge
deCODE genetics, Iceland.
Hreinn
H
Stefánsson
deCODE genetics, Iceland.
Kári
K
Stefánsson
Danish Headache Center, Department of Neurology, Faculty of Health and Medical Sciences, Glostrup Hospital, University of Copenhagen, Denmark jes.olesen@regionh.dk.
Jes
J
Olesen
D000328:Adult; D000700:Analgesics / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics*; D014363:Tryptamines / Q000627:therapeutic use
D000700:Analgesics; D004268:DNA-Binding Proteins; C416371:PRDM16 protein, human; D058825:Serotonin 5-HT1 Receptor Agonists; D014157:Transcription Factors; D014363:Tryptamines
Migraine; drug response; migraine genetics; migraine treatment; triptans