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Background <p>Medication overuse headache (MOH) causes substantial disability in suffering patients, significantly reducing the quality of life. It may lead to structural and functional brain changes detectable by neuroimaging. Successful and effective treatments can alleviate headache burden, reduce consumption of abused drugs and reverse the biological alterations. Therefore, improvement of therapeutic strategies and optimization of patient stratification to match the individuals who can benefit with certain approaches, is essential. This study investigates DNA methylation (DNAm) associated with response to MOH treatment.</p> Methods <p>This analysis was performed within the frame of Epimode project - prospective quantitative longitudinal observational study of genome-wide DNA methylation in neurological cohort. 18 MOH patients, in age range between 33 and 66 years, received treatment which included education on diagnosis, recommendation to stop overused drugs and eventually 5-day inpatient withdrawal program. The effectiveness of MOH therapy was evaluated based on (a) overuse outcome (remission or persistence of MOH diagnosis) and (b) mitigating effect (reversal from chronic to episodic headache attacks), both assessed after 5 months from the enrolment. Genome-wide DNA methylation assay was performed (Infinium Human MethylationEPIC BeadChip, Illumina) in whole blood samples collected at baseline and after 3, 5 and 9 months from enrolment.</p> Results <p>Performed DNAm differential analysis identified methylation signatures linked to MOH treatment and revealed genes involved in epigenetic regulation of response. Among the others, we found <i>PTPRN2</i>, <i>RHOJ</i>, <i>PCDH</i>-γs, <i>CACNA</i> family and <i>SLC38A4</i> genes as associated with MOH overuse outcome; <i>MUC4</i> and <i>FKBP11</i> - as related to mitigating effect of the intervention; and <i>FMOD</i> or <i>ZDHHC14</i> which resulted linked to both endpoints. We observed that differential methylation signal seemed to predominantly capture the changes associated to excessive use of acute medications. Pathway enrichment analysis demonstrated that the genes with differential methylation signal might be involved in pathways related to (i) metabolic detoxification and (ii) neuropsychiatric/behavioral regulation.</p> Conclusions <p>Our findings describe methylation patterns, genes and pathways that may be associated with response to MOH intervention.</p>

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DNA methylation signatures of treatment response in medication-overuse headache

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Katarzyna Malgorzata Kwiatkowska,
  • Valentina Favoni,
  • Francesca Ferraresi,
  • Chiara Pirazzini,
  • Francesco Ravaioli,
  • Maria Giulia Bacalini,
  • Daniele Dall’Olio,
  • Claudia Sala,
  • Gastone Castellani,
  • Luciano Calzari,
  • Davide Gentilini,
  • Rossana Terlizzi,
  • Giulia Pierangeli,
  • Pietro Cortelli,
  • Davide Mascarella,
  • Paolo Garagnani,
  • Sabina Cevoli

摘要

Background

Medication overuse headache (MOH) causes substantial disability in suffering patients, significantly reducing the quality of life. It may lead to structural and functional brain changes detectable by neuroimaging. Successful and effective treatments can alleviate headache burden, reduce consumption of abused drugs and reverse the biological alterations. Therefore, improvement of therapeutic strategies and optimization of patient stratification to match the individuals who can benefit with certain approaches, is essential. This study investigates DNA methylation (DNAm) associated with response to MOH treatment.

Methods

This analysis was performed within the frame of Epimode project - prospective quantitative longitudinal observational study of genome-wide DNA methylation in neurological cohort. 18 MOH patients, in age range between 33 and 66 years, received treatment which included education on diagnosis, recommendation to stop overused drugs and eventually 5-day inpatient withdrawal program. The effectiveness of MOH therapy was evaluated based on (a) overuse outcome (remission or persistence of MOH diagnosis) and (b) mitigating effect (reversal from chronic to episodic headache attacks), both assessed after 5 months from the enrolment. Genome-wide DNA methylation assay was performed (Infinium Human MethylationEPIC BeadChip, Illumina) in whole blood samples collected at baseline and after 3, 5 and 9 months from enrolment.

Results

Performed DNAm differential analysis identified methylation signatures linked to MOH treatment and revealed genes involved in epigenetic regulation of response. Among the others, we found PTPRN2, RHOJ, PCDH-γs, CACNA family and SLC38A4 genes as associated with MOH overuse outcome; MUC4 and FKBP11 - as related to mitigating effect of the intervention; and FMOD or ZDHHC14 which resulted linked to both endpoints. We observed that differential methylation signal seemed to predominantly capture the changes associated to excessive use of acute medications. Pathway enrichment analysis demonstrated that the genes with differential methylation signal might be involved in pathways related to (i) metabolic detoxification and (ii) neuropsychiatric/behavioral regulation.

Conclusions

Our findings describe methylation patterns, genes and pathways that may be associated with response to MOH intervention.