Migraines affect nearly 40 million people in the U.S. Yet pinpointing an effective prophylactic medication ― the most commonly prescribed drugs for people diagnosed with migraines ― remains a long and complex process. Patients often cycle through medications for weeks or months until achieving a therapeutic response. 

Now after years of slow progress in migraine therapies and advancements, a Mayo Clinic Center for Individualized Medicine researcher has discovered variants in six genes that could shed light on what triggers the debilitating condition and provide a potential step toward guiding individualized treatments. 

The new research, led by Fred Cutrer, M.D., a Mayo Clinic neurologist, is published in Molecular Genetics & Genomic Medicine.

"Our study is based on the assumption that the seven chemically and therapeutically very distinct types of medication that are used in migraine prevention exert a biological effect that stabilizes or compensates for the biological cause of a patient’s migraine attacks," explains Dr. Cutrer, who has treated patients with complex headache syndromes for more than 25 years. "This study is the first step toward identifying and treating the biological cause in each individual patient."

A migraine is a headache that can cause severe throbbing pain or a pulsing sensation, usually on one side of the head. It is often accompanied by nausea, vomiting and extreme sensitivity to light and sound. Migraine attacks can last for hours to days, and the pain can be so severe that it interferes with a person's daily activities.

"This study is the first step toward identifying and treating the biological cause in each individual patient." - Dr. Cutrer

For the study, Dr. Cutrer and his team compared the exomes of people whose migraines were greatly reduced by verapamil, a migraine-preventive medicine, to the exomes of people who received the same dose of verapamil but showed little to no improvement. An exome is the part of a patient's genome ―the complete set of genes ― that codes the cells in a person's body, including in the brain where a migraine attack is likely to start.

"We looked for variants in the genetic code that were present in the responders but not the nonresponders," explains Dr. Cutrer. "We then double-checked the variants we had discovered by genotyping the variants in a large validation cohort of different subjects from whom we also had treatment response data."

The team discovered alterations in six genes that they found were highly statistically associated with response to verapamil.

"Our pathway analyses of the identified variants implicated alterations in the cellular function of people who responded to verapamil compared to those who did not respond," Dr. Cutrer says.

Dr. Cutrer says the findings provide vital information for understanding how the drug works in migraine and makes it possible to craft new treatments without unnecessary side effects.

"The findings could also lead to the development of a genetic biomarker test that will guide physicians to prescribe the prophylactic treatment most likely to work in the individual patient," Dr. Cutrer explains. "We can give it to them as the first drug rather than the fourth or fifth."

Overall, the team analyzed genetic samples of nearly 6,000 patients with migraines. They plan to study and sequence additional samples from Mayo Clinic's migraine biorepository, the largest of its kind in the U.S., to analyze other anti-migraine preventive therapies.

Personalizing medicine with pharmacogenomics

Researchers in Mayo Clinic's Center for Individualized Medicine are leaders in pharmacogenomics, which combines the science of drugs and the study of genes to provide patients with safe medications and doses.

Richard Weinshilboum, M.D., interim director for the Center for Individualized Medicine, is helping to lead Mayo's efforts to integrate pharmacogenomics into clinical practice. He says Dr. Cutrer's study is just one example of how the center is working to improve treatments and reduce harmful side effects.

"Dr. Cutrer and his team are to be congratulated for their decades of effort to understand the role of genomics in the cause and individual variation in response to treatment of migraine headaches," Dr. Weinshilboum says. "By using a drug ― in this case verapamil ― as a 'molecular probe,' they have taken a major step forward in our understanding and treatment of this terrible disorder."

Dr. Weinshilboum says, in the near future at Mayo Clinic, genomic test results for most patients will be part of their electronic health record, allowing physicians to use the information to individualize care.

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