title: OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study.
abstract: Majority of the heroin-dependent patients smoke cigarettes. Although it has been reported that the OPRM1 genetic polymorphism is associated with the brain mu-opioid receptor binding potential in cigarette smokers, there is no direct evidence showing the impact of plasma cotinine, a nicotine metabolite, on treatment responses to methadone maintenance treatment (MMT). In this study, we aimed to test the hypothesis that the genetic polymorphisms in the OPRM1 are associated with the methadone treatment responses and the severity of cigarette smoking directly measured by the plasma concentration of cotinine in a Taiwanese MMT cohort. Fifteen OPRM1 single-nucleotide polymorphisms (SNPs) were selected and genotyped on DNA samples of 366 MMT patients. Plasma concentrations of cotinine were measured by cotinine enzyme-linked immunosorbent assay. The plasma cotinine concentration had positive correlation with concentrations of methadone (P = 0.042) and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine (P = 0.037). Methadone treatment non-responders, defined by a positive urine morphine test, had a higher plasma concentration of cotinine (P = 0.005), but a lower plasma concentration-to-dose ratio of both R- and S-methadone (P = 0.001 and 0.012, respectively) than the responders. OPRM1 genetic variants, rs1074287, rs6912029, rs1799971, rs12209447, rs510769, rs3798676, rs553202, rs7748401, rs495491, rs10457090, rs589046, rs3778152 and rs563649, were significantly associated with the plasma concentration of cotinine when using recessive model for genotypes (general linear model (GLM), P<0.038; false discovery rate (FDR)<0.035) and additive model for allele types (GLM, P<0.03; FDR<0.049) in association analyses. The G allele carriers of SNP rs1799971 (A118G) on exon 1 of OPRM1 gene had a lower plasma cotinine concentration than the A allele carriers (GLM, P = 0.029). OPRM1 genetic polymorphisms are associated with the plasma concentration of cotinine in a Taiwanese MMT cohort. Carriers with the major allele of SNP rs1799971 had a higher plasma cotinine concentration.
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Tsou
authors.forename: Hsiang-Wei
authors.initials: HW
authors.lastname: Kuo
authors.forename: Chiu-Ping
authors.initials: CP
authors.lastname: Fang
authors.forename: Sheng-Chang
authors.initials: SC
authors.lastname: Wang
authors.forename: Ing-Kang
authors.initials: IK
authors.lastname: Ho
authors.forename: Yao-Sheng
authors.initials: YS
authors.lastname: Chang
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Chen
authors.forename: Chin-Fu
authors.initials: CF
authors.lastname: Hsiao
authors.forename: Hsiao-Yu
authors.initials: HY
authors.lastname: Wu
authors.forename: Keh-Ming
authors.initials: KM
authors.lastname: Lin
authors.forename: Andrew Ch
authors.initials: ACh
authors.lastname: Chen
authors.forename: Jyy-Jih
authors.initials: JJ
authors.lastname: Tsai-Wu
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Liu
mesh_terms: D000328:Adult; D003367:Cotinine / Q000097:blood*; D003430:Cross-Sectional Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008691:Methadone / Q000008:administration & dosage*; D008875:Middle Aged; D009538:Nicotine / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D017450:Receptors, Opioid, mu / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D009538:Nicotine; D003367:Cotinine; D008691:Methadone