New genetic findings in migraine: So what?

LONDON – The recent discovery of the first four genetic susceptibility loci for migraine without aura has zero clinical relevance today for migraine patients or their physicians, according to experts on migraine genetics.

"Whenever there is a new genetic study, you can easily become almost convinced that now we have the gene and we can treat migraine better. No! Currently there is no indication to test migraine patients for specific genes. It wouldn’t help you at all in terms of treatment or prognosis," Dr. Tobias Kurth emphasized at the European Headache and Migraine Trust International Congress.

"Make no mistake: We have achieved a lot over the last years, and many groups continue to do extraordinary work. However, we all have to realize that we still don’t know the precise mechanisms involved in genetic markers of migraine. We haven’t really shown that having these genes is a predictive tool that can tell patients that they will get migraine, or if they have it what their disease course will be," added Dr. Kurth, director of research at the French National Institute of Health and Medical Research, Bordeaux.

Dr. Arn M.J.M. van den Maagdenberg, a coauthor of the recently published genomewide association study that identified the first four susceptibility loci for migraine without aura (Nat. Gen. 2012;44:777-82), presented highlights of the ambitious study, which was carried out by the International Headache Genetics Consortium. The study involved testing 2,326 headache clinic patients with migraine without aura and 4,580 matched controls for roughly 500,000 genetic variants. The investigators then confirmed their results in a separate replication cohort composed of 2,508 patients with migraine without aura and 2,652 controls.

Dr. van den Maagdenberg was quick to agree that the results aren’t clinically relevant, in part because the four genes explain only a small portion of the genetic variance in migraine. However, the findings do implicate specific pathways of importance in the disease process, he noted.

"You can plot these four genes in three different pathways: neuronal, vascular, and pain. You may think you already knew that these pathways are important in migraine, but now we have molecular proof that migraine patients do indeed have genes that predispose them to migraine based on these pathways. Of course, we’ll need to do a lot of further studies of different kinds in order to identify the mechanisms involved," said Dr. van den Maagdenberg of Leiden (the Netherlands) University.

Of the four novel migraine genes, three – MEF2D, ASTN2, and PHACTR1 – are involved in the neuronal pathway. PHACTR1 also figures in the vascular pathway of migraine. And TGFBR2 plays roles in both the vascular and pain pathways, according to the neurologist.

Dr. Kurth has personal experience in fielding overreaction to genetic study findings, both by the public and by health professionals. He was a coinvestigator in a much-publicized report from the Women’s Genome Health Study that identified five single nucleotide polymorphisms (SNPs), or susceptibility loci, that may be associated with increased risk of cardiovascular events in women with migraine.

This was a genomewide association study of 5,122 women with migraine who were followed for 12 years as part of the National Institutes of Health–sponsored Women’s Health Study. One susceptibility locus was associated with a statistically significant and sky-high 12.3-fold risk of cardiovascular death during follow-up. Two others were linked to impressive-sounding 5- and 6.4-fold increased risks of ischemic stroke in women with migraine with aura (PLoS One 2011;6:e22106). But neither Dr. Kurth nor his coworkers really believe those numbers.

"Those odds ratios look quite high, but the number of outcome events is extraordinarily small here: 164 cardiovascular events in 12 years. So despite the statistical significance, these odds ratios are completely meaningless. We have to be extremely careful not to say that these genes are actually the cause of women with migraine getting cardiovascular disease. This is a hypothesis-generating study," Dr. Kurth explained.

Dr. Kurth and Dr. van den Maagdenberg reported having no financial conflicts.

LONDON – The recent discovery of the first four genetic susceptibility loci for migraine without aura has zero clinical relevance today for migraine patients or their physicians, according to experts on migraine genetics.

"Whenever there is a new genetic study, you can easily become almost convinced that now we have the gene and we can treat migraine better. No! Currently there is no indication to test migraine patients for specific genes. It wouldn’t help you at all in terms of treatment or prognosis," Dr. Tobias Kurth emphasized at the European Headache and Migraine Trust International Congress.

"Make no mistake: We have achieved a lot over the last years, and many groups continue to do extraordinary work. However, we all have to realize that we still don’t know the precise mechanisms involved in genetic markers of migraine. We haven’t really shown that having these genes is a predictive tool that can tell patients that they will get migraine, or if they have it what their disease course will be," added Dr. Kurth, director of research at the French National Institute of Health and Medical Research, Bordeaux.

Dr. Arn M.J.M. van den Maagdenberg, a coauthor of the recently published genomewide association study that identified the first four susceptibility loci for migraine without aura (Nat. Gen. 2012;44:777-82), presented highlights of the ambitious study, which was carried out by the International Headache Genetics Consortium. The study involved testing 2,326 headache clinic patients with migraine without aura and 4,580 matched controls for roughly 500,000 genetic variants. The investigators then confirmed their results in a separate replication cohort composed of 2,508 patients with migraine without aura and 2,652 controls.

Dr. van den Maagdenberg was quick to agree that the results aren’t clinically relevant, in part because the four genes explain only a small portion of the genetic variance in migraine. However, the findings do implicate specific pathways of importance in the disease process, he noted.

"You can plot these four genes in three different pathways: neuronal, vascular, and pain. You may think you already knew that these pathways are important in migraine, but now we have molecular proof that migraine patients do indeed have genes that predispose them to migraine based on these pathways. Of course, we’ll need to do a lot of further studies of different kinds in order to identify the mechanisms involved," said Dr. van den Maagdenberg of Leiden (the Netherlands) University.

Of the four novel migraine genes, three – MEF2D, ASTN2, and PHACTR1 – are involved in the neuronal pathway. PHACTR1 also figures in the vascular pathway of migraine. And TGFBR2 plays roles in both the vascular and pain pathways, according to the neurologist.

Dr. Kurth has personal experience in fielding overreaction to genetic study findings, both by the public and by health professionals. He was a coinvestigator in a much-publicized report from the Women’s Genome Health Study that identified five single nucleotide polymorphisms (SNPs), or susceptibility loci, that may be associated with increased risk of cardiovascular events in women with migraine.

This was a genomewide association study of 5,122 women with migraine who were followed for 12 years as part of the National Institutes of Health–sponsored Women’s Health Study. One susceptibility locus was associated with a statistically significant and sky-high 12.3-fold risk of cardiovascular death during follow-up. Two others were linked to impressive-sounding 5- and 6.4-fold increased risks of ischemic stroke in women with migraine with aura (PLoS One 2011;6:e22106). But neither Dr. Kurth nor his coworkers really believe those numbers.

"Those odds ratios look quite high, but the number of outcome events is extraordinarily small here: 164 cardiovascular events in 12 years. So despite the statistical significance, these odds ratios are completely meaningless. We have to be extremely careful not to say that these genes are actually the cause of women with migraine getting cardiovascular disease. This is a hypothesis-generating study," Dr. Kurth explained.

Dr. Kurth and Dr. van den Maagdenberg reported having no financial conflicts.

LONDON – The recent discovery of the first four genetic susceptibility loci for migraine without aura has zero clinical relevance today for migraine patients or their physicians, according to experts on migraine genetics.

"Whenever there is a new genetic study, you can easily become almost convinced that now we have the gene and we can treat migraine better. No! Currently there is no indication to test migraine patients for specific genes. It wouldn’t help you at all in terms of treatment or prognosis," Dr. Tobias Kurth emphasized at the European Headache and Migraine Trust International Congress.

"Make no mistake: We have achieved a lot over the last years, and many groups continue to do extraordinary work. However, we all have to realize that we still don’t know the precise mechanisms involved in genetic markers of migraine. We haven’t really shown that having these genes is a predictive tool that can tell patients that they will get migraine, or if they have it what their disease course will be," added Dr. Kurth, director of research at the French National Institute of Health and Medical Research, Bordeaux.

Dr. Arn M.J.M. van den Maagdenberg, a coauthor of the recently published genomewide association study that identified the first four susceptibility loci for migraine without aura (Nat. Gen. 2012;44:777-82), presented highlights of the ambitious study, which was carried out by the International Headache Genetics Consortium. The study involved testing 2,326 headache clinic patients with migraine without aura and 4,580 matched controls for roughly 500,000 genetic variants. The investigators then confirmed their results in a separate replication cohort composed of 2,508 patients with migraine without aura and 2,652 controls.

Dr. van den Maagdenberg was quick to agree that the results aren’t clinically relevant, in part because the four genes explain only a small portion of the genetic variance in migraine. However, the findings do implicate specific pathways of importance in the disease process, he noted.

"You can plot these four genes in three different pathways: neuronal, vascular, and pain. You may think you already knew that these pathways are important in migraine, but now we have molecular proof that migraine patients do indeed have genes that predispose them to migraine based on these pathways. Of course, we’ll need to do a lot of further studies of different kinds in order to identify the mechanisms involved," said Dr. van den Maagdenberg of Leiden (the Netherlands) University.

Of the four novel migraine genes, three – MEF2D, ASTN2, and PHACTR1 – are involved in the neuronal pathway. PHACTR1 also figures in the vascular pathway of migraine. And TGFBR2 plays roles in both the vascular and pain pathways, according to the neurologist.

Dr. Kurth has personal experience in fielding overreaction to genetic study findings, both by the public and by health professionals. He was a coinvestigator in a much-publicized report from the Women’s Genome Health Study that identified five single nucleotide polymorphisms (SNPs), or susceptibility loci, that may be associated with increased risk of cardiovascular events in women with migraine.

This was a genomewide association study of 5,122 women with migraine who were followed for 12 years as part of the National Institutes of Health–sponsored Women’s Health Study. One susceptibility locus was associated with a statistically significant and sky-high 12.3-fold risk of cardiovascular death during follow-up. Two others were linked to impressive-sounding 5- and 6.4-fold increased risks of ischemic stroke in women with migraine with aura (PLoS One 2011;6:e22106). But neither Dr. Kurth nor his coworkers really believe those numbers.

"Those odds ratios look quite high, but the number of outcome events is extraordinarily small here: 164 cardiovascular events in 12 years. So despite the statistical significance, these odds ratios are completely meaningless. We have to be extremely careful not to say that these genes are actually the cause of women with migraine getting cardiovascular disease. This is a hypothesis-generating study," Dr. Kurth explained.

Dr. Kurth and Dr. van den Maagdenberg reported having no financial conflicts.