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PLoS Genet. 2016 Mar 24;12(3):e1005910. doi: 10.1371/journal.pgen.1005910. eCollection 2016 Mar.

Genome-Wide Pharmacogenomic Study on Methadone Maintenance Treatment Identifies SNP rs17180299 and Multiple Haplotypes on CYP2B6, SPON1, and GSG1L Associated with Plasma Concentrations of Methadone R- and S-enantiomers in Heroin-Dependent Patients.

Yang HC1,2,3,4,5, Chu SK1,2,6, Huang CL7,8, Kuo HW9, Wang SC9, Liu SW9, Ho IK7, Liu YL9,10.

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Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, Taiwan.
Institute of Public Health, National Yang Ming University, Taipei, Taiwan.
Department of Statistics, National Cheng-Kung University, Tainan, Taiwan.
School of Public Health, National Defense Medical Center, Taipei, Taiwan.
Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung, Taiwan.
School of Medicine, China Medical University, Taichung, Taiwan.
Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan.
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.


Methadone maintenance treatment (MMT) is commonly used for controlling opioid dependence, preventing withdrawal symptoms, and improving the quality of life of heroin-dependent patients. A steady-state plasma concentration of methadone enantiomers, a measure of methadone metabolism, is an index of treatment response and efficacy of MMT. Although the methadone metabolism pathway has been partially revealed, no genome-wide pharmacogenomic study has been performed to identify genetic determinants and characterize genetic mechanisms for the plasma concentrations of methadone R- and S-enantiomers. This study was the first genome-wide pharmacogenomic study to identify genes associated with the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites in a methadone maintenance cohort. After data quality control was ensured, a dataset of 344 heroin-dependent patients in the Han Chinese population of Taiwan who underwent MMT was analyzed. Genome-wide single-locus and haplotype-based association tests were performed to analyze four quantitative traits: the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites. A significant single nucleotide polymorphism (SNP), rs17180299 (raw p = 2.24 × 10(-8)), was identified, accounting for 9.541% of the variation in the plasma concentration of the methadone R-enantiomer. In addition, 17 haplotypes were identified on SPON1, GSG1L, and CYP450 genes associated with the plasma concentration of methadone S-enantiomer. These haplotypes accounted for approximately one-fourth of the variation of the overall S-methadone plasma concentration. The association between the S-methadone plasma concentration and CYP2B6, SPON1, and GSG1L were replicated in another independent study. A gene expression experiment revealed that CYP2B6, SPON1, and GSG1L can be activated concomitantly through a constitutive androstane receptor (CAR) activation pathway. In conclusion, this study revealed new genes associated with the plasma concentration of methadone, providing insight into the genetic foundation of methadone metabolism. The results can be applied to predict treatment responses and methadone-related deaths for individualized MMTs.

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