The μ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3' untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.

译文

:μ阿片受体(MOR)是美沙酮和丁丙诺啡的主要靶标。 OPRM1基因的主要神经元转录物MOR-1包含一个〜13 kb 3'非翻译区,在欧美人中有五种常见的单倍型。我们在美沙酮或丁丙诺啡/纳洛酮(Suboxone)治疗阿片类药物的24周随机,开放标签试验中,分析了这些单倍型对欧洲裔美国人(n = 582)阿片类药物阳性尿检百分比的影响依赖。在美沙酮治疗组中,一个由rs10485058标记的单倍型与患者尿液分析数据显着相关。具有A / A基因型rs10485058的美沙酮患者比具有A / G和G / G联合基因型组的患者接受阿片类药物阳性尿液筛查的可能性更低(相对风险= 0.76,95%置信区间= 0.73-0.80, P = 0.0064)。 rs10485058的基因型还预测了接受阿片类药物替代治疗的欧洲裔澳大利亚独立患者(n = 1215)的自我报告的复发率(P = 0.003)。在计算机分析中预测,miR-95-3p将与rs10485058的G等位基因相互作用,但不会与之相互作用。萤光素酶分析表明,miR-95-3p降低了含有rs10485058的G等位基因的构建体的报告基因活性,提示观察到的药理作用的潜在机制。这些发现表明,基于rs10485058基因型的阿片类药物依赖药物的选择可能会改善该族群的结局。

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