期刊
MOLECULAR PSYCHIATRY
卷 22, 期 3, 页码 346-352出版社
SPRINGERNATURE
DOI: 10.1038/mp.2016.257
关键词
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资金
- National Institutes of Health (NIH) [RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, MSTP 5T32GM007205- 38, CTSA TL1 8UL1TR000142, F30 DA037665, N01-HG-65403, S10 RR19895]
- Veterans Affairs VISN1 Career Development Award
- Department of Anesthesiology and Critical Care Medicine at Children's Hospital of Philadelphia through Children's Anesthesia Associates, Ltd.
- Children's Hospital of Philadelphia through from the Institutional Development Fund
Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the mu-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study of usual daily methadone dose. In African-American (AA) OD subjects (n = 383), we identified a genome-wide significant association between therapeutic methadone dose (mean = 68.0 mg, s.d. = 30.1 mg) and rs73568641 (P = 2.8 x 10(-8)), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional similar to 20 mg day(-1) of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n = 1027), no genome-wide significant associations with methadone dose (mean = 77.8 mg, s.d. = 33.9 mg) were observed. In an independent set of opioid-naive AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n = 241, P = 3.9 x 10(-2)). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n = 1410, genetic score P = 1.3 x 10(-3)). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction.
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