title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hsin-Chou
authors.initials: HC
authors.lastname: Yang
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.|Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, Taiwan.|Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Kai
authors.initials: SK
authors.lastname: Chu
authors.affiliation: Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung, Taiwan.|School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chieh-Liang
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan.
authors.forename: Hsiang-Wei
authors.initials: HW
authors.lastname: Kuo
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan.
authors.forename: Sheng-Chang
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan.
authors.forename: Sheng-Wen
authors.initials: SW
authors.lastname: Liu
authors.affiliation: Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ing-Kang
authors.initials: IK
authors.lastname: Ho
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Liu
mesh_terms: D000328:Adult; D000731:Androstanes / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D003932:Heroin / Q000378:metabolism / Q000633:toxicity; D006556:Heroin Dependence / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008691:Methadone / Q000008:administration & dosage* / Q000378:metabolism; D008875:Middle Aged; D058850:Opiate Substitution Treatment; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013237:Stereoisomerism
chemical_list: D000731:Androstanes; D016326:Extracellular Matrix Proteins; C429104:SPON1 protein, human; D003932:Heroin; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C033936:androstane; D008691:Methadone