Variability of Response to Methadone: Genome-Wide DNA Methylation Analysis in Two Independent Cohorts

Abstract

Aim: Methadone maintenance treatment is characterized by large interindividual dose variability. The aim of this study was to evaluate whether DNA methylations are associated with daily dose of methadone. Materials & methods: Subjects stabilized at high (n = 12) or low (n = 12) methadone doses were selected from two independent cohorts (French and Swiss). DNA methylation patterns were analyzed using HumanMethylation450 BeadChips. Results: In total, 584 differentially methylated sites were identified in the French cohort corresponding to 352 genes. Of these, 26 were replicated in the Swiss cohort. The methylation status of 13 genes varied similarly in both cohorts and calcium signaling pathway was significantly enriched. Conclusion: Our results indicate that differentially methylated sites are associated with methadone daily dose and give insights into the molecular pathways underlying this interindividual dose variability.

Keywords::

• addiction
• biomarkers
• DNA methylation
• epigenetics
• heroin
• methadone

Financial & competing interests disclosure

The work on the French cohort was supported by a grant from the Direction de la Recherche Clinique et du Developpement de l’Assistance Publique-Hopitaux de Paris (DRCD) in 2007 (#OST07013) and by the Mission interministérielle de lutte contre la drogue et la toxicomanie (MILDT) in 2006 (grant #ASE07082KSA). The work on the Swiss cohort was supported by the Swiss National Research Foundation (project 3200-065427.01) and Swiss Federal Office of Public Health (project 02.001382). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The work on the French cohort was supported by a grant from the Direction de la Recherche Clinique et du Developpement de l’Assistance Publique-Hopitaux de Paris (DRCD) in 2007 (#OST07013) and by the Mission interministérielle de lutte contre la drogue et la toxicomanie (MILDT) in 2006 (grant #ASE07082KSA). The work on the Swiss cohort was supported by the Swiss National Research Foundation (project 3200-065427.01) and Swiss Federal Office of Public Health (project 02.001382). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.