Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Drug Alcohol Depend. 2013 Jan 1;127(1-3):122-8. doi: 10.1016/j.drugalcdep.2012.06.023. Epub 2012 Jul 12.
Addiction susceptibility and treatment responsiveness are greatly influenced by genetic factors. Sequence variation in genes involved in the mechanisms of drug action have the potential to influence addiction risk and treatment outcome. The opioid receptor system is involved in mediating the rewarding effects of cocaine and opioids. The μ-opioid receptor (MOR) has traditionally been considered the primary target for opioid addiction. The MOR, however, interacts with and is regulated by many known MOR interacting proteins (MORIPs), including the δ-opioid receptor (DOR).
The present study evaluated the contribution of OPRD1, the gene encoding the DOR, to the risk of addiction to opioids and cocaine. The association of OPRD1 polymorphisms with both opioid addiction (OA) and cocaine addiction (CA) was analyzed in African American (OA n=336, CA n=503) and European American (OA n=1007, CA n=336) populations.
The primary finding of this study is an association of rs678849 with cocaine addiction in African Americans (allelic p=0.0086). For replication purposes, this SNP was analyzed in a larger independent population of cocaine addicted African Americans and controls and the association was confirmed (allelic p=4.53 × 10(-5); n=993). By performing a meta-analysis on the expanded populations, the statistical evidence for an association was substantially increased (allelic p=8.5 × 10(-7)) (p-values non-FDR corrected).
The present study suggests that polymorphisms in OPRD1 are relevant for cocaine addiction in the African American population and provides additional support for a broad role for OPRD1 variants in drug dependence.
成瘾易感性和治疗反应性受遗传因素的影响很大。参与药物作用机制的基因中的序列变异有可能影响成瘾风险和治疗结果。阿片受体系统参与介导可卡因和阿片类药物的奖赏效应。μ-阿片受体（MOR）传统上被认为是阿片类药物成瘾的主要靶点。然而，MOR 与许多已知的 MOR 相互作用蛋白（MORIP）相互作用并受其调节，包括δ-阿片受体（DOR）。
本研究评估了编码 DOR 的 OPRD1 基因对阿片类药物和可卡因成瘾风险的贡献。分析了 OPRD1 多态性与阿片类药物成瘾（OA）和可卡因成瘾（CA）的关系，在非裔美国人（OA n=336，CA n=503）和欧洲裔美国人（OA n=1007，CA n=336）人群中进行。
本研究的主要发现是 rs678849 与非裔美国人可卡因成瘾相关（等位基因 p=0.0086）。为了复制目的，该 SNP 在一个更大的独立的可卡因成瘾的非裔美国人群和对照组中进行了分析，该关联得到了确认（等位基因 p=4.53×10(-5)；n=993）。通过对扩展人群进行荟萃分析，关联的统计证据大大增加（等位基因 p=8.5×10(-7)）（未校正 FDR 的 p 值）。
本研究表明，OPRD1 多态性与非裔美国人可卡因成瘾有关，并为 OPRD1 变体在药物依赖中的广泛作用提供了额外的支持。
