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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Androstanes / metabolism
  • Cytochrome P-450 CYP2B6 / genetics*
  • Extracellular Matrix Proteins / genetics*
  • Female
  • Genome-Wide Association Study
  • Haplotypes / genetics
  • Heroin / metabolism
  • Heroin / toxicity
  • Heroin Dependence / genetics*
  • Heroin Dependence / metabolism
  • Heroin Dependence / pathology
  • Humans
  • Male
  • Methadone / administration & dosage*
  • Methadone / metabolism
  • Middle Aged
  • Opiate Substitution Treatment
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide
  • Stereoisomerism

Substances

  • Androstanes
  • Extracellular Matrix Proteins
  • SPON1 protein, human
  • Heroin
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • androstane
  • Methadone

Grant support

HCY was supported by grants from the Ministry of Science and Technology of Taiwan (MOST 103-2314-B-001-008-MY3 and NSC100-2314-B-001-005-MY3) and the Career Development Award of Academia Sinica (AS-100-CDA-M03). YLL was supported by grants from the National Research Program for Genomic Medicine [NSC 100-3112-B-400-015], National Science Council [NSC 100-2314-B-400-002-MY3] and the National Health Research Institutes, Taiwan [NP-104-PP-04, NP-105-PP-04, NP-104-SP-04 and NP-105-SP-04]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.