Response to Methadone Maintenance Treatment is Associated with the MYOCD and GRM6 Genes
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ORIGINAL RESEARCH ARTICLE
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Response to Methadone Maintenance Treatment is Associated with the MYOCD and GRM6 Genes Francina Fonseca,1 Mo`nica Grataco`s,2 Geo`rgia Escaramı´s,2 Rafael De Cid,2,3 Rocı´o Martı´n-Santos,4,5 Emilio Ferna´ndez-Espejo,6 Xavier Estivill2,3,7 and Marta Torrens1,8 1 2 3 4 5 6 7 8
Institut de Neuropsiquiatria i Addiccions-Parc de Salut Mar, Barcelona, Spain CIBER Epidemiologı´a y Salud Pu´blica (CIBERESP) and Genes and Disease Program, Barcelona, Spain National Center of Genotyping (CeGen), Center for Genomic Regulation (CRG), Barcelona, Spain Service of Psychiatry, Neuroscience Institute, Hospital Clinic, IDIBAPS, CIBERSAM, Barcelona, Spain Pharmacology Unit, Institut Mar d’Investigacio´ Me`dica, IMIM-Parc de Salut Mar, Barcelona, Spain Department of Medical Physiology, University of Seville, Seville, Spain Experimental and Health Sciences Department, Pompeu Fabra University, Barcelona, Spain Psychiatric Department, Autonomous University of Barcelona, Barcelona, Spain
Abstract
Background: There is increasing interest in the pharmacogenetic basis for explaining differences between patients in treatment outcome among methadone-treated subjects. Most studies have focused on genetic polymorphisms related to methadone pharmacokinetics and, to a lesser extent, those genes implicated in the pharmacodynamics of methadone. Objective: This study aimed to investigate the associations between response to methadone maintenance treatment (MMT) and polymorphisms in genes coding for the OPRM1 opioid receptor, the metabotropic glutamate receptors GRM6 and GRM8, the nuclear receptor NR4A2, the photolyase enzyme cryptochrome 1 (CRY1), and the transcription factor myocardin (MYOCD), which have previously been associated with the risk of opioid dependence disorder. Methods: The study used an association, case-control design, conducted in the setting of an MMT program in a drug abuse outpatient center in Barcelona, Spain. We recruited 169 opioid-dependent patients (diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders [4th Edition] criteria) receiving MMT. The inclusion criteria included Caucasian ethnicity, being enrolled in MMT for at least 6 months, and receiving a stable methadone dose for the previous 2 months. The exclusion criteria included language-related barriers, severe cognitive impairment, or any medical disorder that would interfere with the research assessments. Single nucleotide polymorphism (SNP) variants in several candidate genes and regions were genotyped: MYOCD (rs1714984), GRM8 (rs1034576), CRY1 (rs1861591), GRM6 (rs953741), OPRM1 (rs1074287), NR4A2 (rs1405735), and the intergenic variants rs965972 (1q31.2) and rs1867898 (2q21.2). MMT response status was assessed by the number of opioid-positive controls detected by random urinalysis in the previous 2 months. We used the chi-squared test and p-value for the allele frequencies of the eight SNPs in responders versus nonresponders, and multivariate logistic reg
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