Chronic migraine research finds genetic mechanism to lower migraine frequency

DNA detectives from QUT have found a biological mechanism behind the reduction of migraine frequency in chronic migraine sufferers after their gradual withdrawal from migraine medications.

  • Two genes with epigenetic changes associated with a reduction in headaches and migraine
  • Overuse of acute medication such as pain relief can cause and maintain chronic migraine
  • Gradual withdrawal from acute migraine medications found to return chronic migraine to episodic levels
  • The two genes could be therapeutic targets for migraine

The study ‘Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study‘ was published in Clinical Epigenetics and describes the finding of epigenetic changes in two genes implicated in the transition from episodic migraines to chronic migraine.

First author QUT geneticist Professor Divya Mehta from QUT’s Centre for Genomics and Personalised Health in the School of Biomedical Sciences and QUT’s Centre for Data Science said chronic migraine was a major headache for about 2 per cent of the general population.

“Overuse of acute headache pain relief and other medications is an important factor in the development and maintenance of chronic migraine,” Professor Mehta said.

“We class migraine as chronic if the sufferer has headaches on 15 or more days a month for three or more months of which eight days fulfil migraine criteria, so it is a highly disabling type of migraine.

“Working with colleagues at Leiden University Medical Centre (LUMC) in the Netherlands, we set out to understand the process of migraine chronification whereby attacks become more and more frequent in some migraine sufferers and how this process could be reversed.

From left: Charlotte Bainomugasa, Professor Divya Mehta, Professor Dale Nyholt, Associate Professor Larisa Haupt, and Dr Heidi Sutherland. Top inset: Distinguished Professor Lyn Griffiths, lower inset: Charlene Bron

“The research team investigated longitudinal changes in DNA methylation, an epigenetic modification, which are chemical ‘tags’ added to DNA molecules in response to environmental factors, including therapeutic drugs, that ‘switch’ genes on or off.”

Co-first author and researcher molecular biologist and geneticist Dr Heidi Sutherland from QUT’s Centre for Genomics and Personalised Health and School of Biomedical Sciences said DNA was analysed from blood taken from the patients with chronic migraine at the beginning of and after the 12-week withdrawal from medication treatment.

“The patients kept a headache diary and those who had a greater than 50 per cent reduction in monthly headache and migraine days (the responders) were compared with the non-responders to identify DNA methylation changes associated with their response to treatment,” Dr Sutherland said.

“Of all the patients, 59.8 per cent had reverted to episodic migraine by the end of the 12-week withdrawal period.

“We found epigenetic changes in the HDAC4 gene that were associated with a mean reduction in headache days following the withdrawal of acute medication and that decreased DNA methylation levels were associated with reduced headache days.

“Secondly, we found that DNA methylation within the MARK3 gene was associated with a mean reduction in migraine days. Lower DNA methylation levels at baseline in MARK3 was associated with reduced monthly migraine days and found to be a biomarker to predict response.

Professor Mehta said the findings had huge clinical implications as they indicated that these genes might be novel therapeutic targets for migraine.

The study was jointly led by Distinguished Professor Lyn Griffiths and Professor Dale Nyholt from QUT and Professor Gisela Terwindt from Leiden University Medical Centre.

The QUT researchers on this study were: Professor Mehta, Dr Sutherland, Charlene Bron, Charlotte Bainomugisa, Associate Professor Larisa Haupt, Distinguished Professor Lyn Griffiths, Professor Dale Nyholt, all from QUT Centre for Genomics and Personalised Health.

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