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.

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study

“…Our study confirms the impact of the CYP2B6 genotype on plasma methadone enantiomer concentrations, which was previously reported for (S)‐ methadone and confirmed in a genome‐wide association study (GWAS); CYP2B6 displays stereoselectivity toward (S)‐ methadone . It appears that activity at mu receptors is related to the concentration of (R)‐ methadone.…”

“…Few genome‐wide pharmacogenomics studies have searched for genes involving the regulatory mechanisms of methadone dose, pharmacokinetics, plasma (R) ‐ and (S) ‐enantiomer concentrations, or pharmacodynamic associations with various single nucleotide polymorphisms . However, GWAS that allow identification of new genes associated with methadone dose need a large number of subjects, which is rarely the case in pharmacogenetics studies (Clinical Pharmacogenetics Implementation Consortium, https://cpicpgx.org).…”

Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1

“…Genetic variants at loci related to methadone metabolism may also be clinically relevant, but their study has been complicated by the presence of differently metabolized optical isomers, 55 the use of different experimental paradigms, 20, 21, 56–58 and the possible tissue specificity of enzymatic activity. 59, 60 Our suggestive finding that a CYP2D6 loss of function allele 61, 62 decreases required methadone dose is in the expected direction.…”

The importance of buprenorphine research in the opioid crisis

“…Efficacy can be defined as either reduction in drug use or prevention of relapse, and there are a series of studies that have used this pharmacogenomics approach in the treatment of nicotine and alcohol use disorders [19][20][21][22][23][24][25]. Several studies have also identified variants associated with either the dose or serum concentration of methadone [26][27][28][29][30][31][32]. Metabolism of buprenorphine is variable among individuals suggesting a similar genetic etiology.…”