MU OPIOID RECEPTOR POLYMORPHISMS AND ALCOHOL DEPENDENCE

MU 阿片受体多态性和酒精依赖性

• 批准号: 6431386
• 负责人: DAVID GOLDMAN
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431386
• 关键词: alcoholism /alcohol abuse; behavioral /social science research tag; behavioral genetics; clinical research; gene frequency; genetic polymorphism; genotype; human population genetics; human subject; interview; introns; linkage mapping; nucleic acid sequence; opioid receptor; phenotype

The mu opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse. We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect the function of this receptor or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three amino acid substitutions(Ala6Val [rare], Asn40Asp [frequency 10%], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C [frequency 50%]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (N = 791) were used to perform association and sib-pair linkage analyses to alcohol dependence. There was no significant association or linkage between OPRM1 and alcohol dependence in any of the three population samples. These results and power calculations strongly suggest that variation at the mu opioid receptor is not involved in vulnerability to DSM-III-R Alcohol Dependence. Variation is being investigated for possible association to response to opiate pharmacotherapy and to variation in opioid function, in collaboration with Stephanie O'Malley, Yale University. A study on inherited differences in nociception has been initiated with Ray Dionne & Michael Iadarola of the National Institute of Dental and Craniofacial Research, NIH. A large scale case-control association study on opioid addiction has been completed and these results are in preparation for publication.

μ阿片受体与酒精和其他滥用药物的奖赏、耐受和戒断作用有关。 我们直接对人类μ阿片受体基因座OPRM 1进行测序，以检测可能影响该受体功能或与阿片功能相关的精神病表型相关的自然变异。 发现4种DNA序列变异：3种氨基酸替换（Ala 6Val [罕见]，Asn 40 Asp [频率10%]，Ser 147 Cys [罕见]）和1种内含子变异（IVS 2 + 691 G/C [频率50%]）。 OPRM 1等位基因，基因型和单倍型从三个精神病学特征的人群样本（N = 791）进行关联和同胞对连锁分析，酒精依赖。 在这三个人群样本中，OPRM 1和酒精依赖之间没有显著的关联或联系。 这些结果和功效计算强烈表明，μ阿片受体的变异与DSM-III-R酒精依赖的易感性无关。 与耶鲁大学Stephanie O 'Malley合作，正在研究变异与阿片类药物治疗反应和阿片类药物功能变异的可能关联。 美国国立卫生研究院牙科和颅面研究所的Ray Dionne和Michael Iadarola发起了一项关于伤害感受遗传差异的研究。一项关于阿片类药物成瘾的大规模病例对照关联研究已经完成，这些结果正在准备发表。