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.
Highlights
Heroin dependence is a severe psychiatric disorder characterized by a heroin craving behavior and the inability to stop using heroin
The plasma concentration of methadone is a primary index for quantifying and determining therapy responses to maintenance treatment (MMT)
The analysis identified a single nucleotide polymorphism (SNP) marker and 17 haplotypes on the SPON1, GSG1L, and cytochrome P-450 (CYP450) genes, including CYP2B6 significantly associated with the plasma concentrations of methadone enantiomers
Summary
Heroin dependence is a severe psychiatric disorder characterized by a heroin craving behavior and the inability to stop using heroin. The World Health Organization reported that there were more than 9 million heroin users in 2014, and the prevalence of heroin dependence is increasing globally. Heroin abuse can incur medical complications and generate social problems; these problems have substantially increased the burden on social security and health insurance systems [1, 2]. Replacement or maintenance therapy with an opioid analog is among the most commonly used treatments for heroin dependence, and reduces craving and withdrawal symptoms, increases treatment compliance, and improves the quality of life of patients [3]. A synthetic opioid, is a commonly used medication for treating heroin dependence [4]. Methadone maintenance treatment (MMT) reportedly retains patients and decreases heroin use more effectively than no treatment [4,5,6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
