Migraine Susceptibility Not Increased by MTHFR or ACE Polymorphisms

Patient Expert
Medically Reviewed

The search for all of the genes involved in migraine is both fascinating and ongoing. Although many of us are interested in genetic testing for migraine, that testing still can't really give us definitive answers except in the case of hemiplegic migraine. Genetic research into hemiplegic migraine has advanced more than the research into other forms of migraine.

One genetic polymorphism for which some migraineurs have been anxious to test is the methylenetetrahydrofolate reductase (MTHFR) polymorphism. A 2016 study published in Headache concluded that this polymorphism doesn't increase susceptibility to migraine.

Study objective:

"The aim of this study was to confirm previous reports in order to substantiate the hypothesis that functional variants of two genes, namely methylenetetrahydrofolate reductase and angiotensin I converting enzyme, both involved in an important pathway of migraine, increase migraine susceptibility when present in combination."

Study background:

"Migraine is a complex genetic disease. The migraine attack is thought to be the result of an interaction of neuronal and vascular events, possibly originating in the brainstem leading to activation of the pain processing trigeminovascular system. Functional variants in the methylenetetrahydrofolate gene (MTHFR) and the angiotensin I converting enzyme (ACE) have influence on vascular mechanism and have been investigated intensively in migraine. The published results were inconsistent; however, both polymorphisms in combination have been shown to increase migraine susceptibility."

Study methods:

The prevalence of the functionally relevant polymorphisms C677T in the MTHFR gene and I/D polymorphism in the ACE gene was compared in 420 patients with migraine vs 258 migraine-free control patients.

Study results:

"Susceptibility to any type of migraine (migraine with aura, migraine without aura, and both types combined) was neither increased by each polymorphism on its own, nor in combination."

Study conclusions:

"We could not replicate previous findings which demonstrated that two functional polymorphisms, namely MTHFR C677T and ACE I/D, influence migraine susceptibility either alone or in combination. Given the genetic as well as the clinical heterogeneity found in migraine, replication of associations in separate samples is of utmost importance. Progress in methodology will probably help to entangle the complexity of common complex genetic disorders like migraine in the near future."

Comments and implications for patients:

Identification of the genetic polymorphisms involved in migraine could bring many advances to the diagnosis and treatment of migraine disease. Genetics could open the door to a diagnostic test to confirm migraine, determining with certainty the form of migraine that patients have, and even genetically target treatments. Research has yet to sufficiently identify those polymorphisms, however, and for the most part, genetic testing for migraine is expensive and inconclusive.


Essmeister R, Kress H, Zierz S. MTHFR and ACE Polymorphisms Do Not Increase Susceptibility to Migraine Neither Alone Nor in Combination. Headache 2016;56:1267-1273.