Divya Mehta (Queensland/ AU), Irene de Boer (Leiden/ NL), Heidi Sutherland (Brisbane/ AU), Judith Pijpers (Leiden/ NL), Charlene Bron (Brisbane/ AU), Charlotte Bainomugisa (Queensland/ AU), Larisa Haupt (Brisbane/ AU), Arn van den Maagdenberg (Leiden/ NL), Lyn Griffiths (Brisbane/ AU), Dale Nyholt (Brisbane/ AU), Gisela Terwindt (Leiden/ NL; Brisbane/ AU)
Abstract text (incl. figure legends and references)
Objective: The mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. Epigenetic changes are implicated in this process. If treatment results in conversion back to episodic migraine these epigenetic processes might also be reverted. We aimed to identify DNA methylation changes associated with treatment response in chronic migraine patients with medication overuse.
Methods: A longitudinal epigenome-wide association study was performed as part of the Chronification and Reversibility of Migraine (CHARM) study. Blood was taken from chronic migraine patients (n = 98) at baseline and after a 12-week withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify methylation changes associated with treatment response. Similarly, ≥ 50% versus < 50% reduction in monthly migraine days (MMD) was compared. Sex-specific analyses were performed. Finally, it was evaluated whether DNA methylation status at baseline was predictive of treatment response after t = 12 weeks.
Results: At the genome-wide level, a change in DNA methylation at one CpG site within an intron of the HDAC4 gene was associated with MHD response (p = 9.42×10–8) (Fig 1A). Sex-specific analyses revealed two CpG sites associated with MHD response, proximal to DLGAP2 for women (p = 1.11x10-7) and STS5/AKIP1 for men (p = 8.67x10-8). Five CpG sites were associated with MMD response in men: ZAN (p = 2.41x10-8), ZNF248 (p = 2.52x10-8), H4C2 (p = 2.87x10-8), between RIT2/SYT4 (p = 4.29x10-8), and between NRXN1/ASB3 (p = 6.44x10-8). Baseline methylation at one CpG within MARK3 was predictive of MMD response at 12 weeks.
Conclusion: Global and sex-specific DNA methylation changes are associated with treatment response in chronic migraine. Moreover, DNA methylation status at baseline might be predictive of treatment response.