Optimizing naltrexone for individuals of East Asian descent

描述(申请人提供)：最近的药物遗传学研究已经提出了编码阿片受体基因(OPRM1)的基因，作为对纳曲酮反应的潜在调节因子。OPRM1基因研究最广泛的多态是Asn40Asp单核苷酸多态(SNP)，这是一种被认为影响受体活性的功能性突变，Asp40变体与内啡肽的结合强度是Asn40等位基因的三倍。最近的研究发现，Asp40携带者对静脉注射酒精有更强的纹状体多巴胺反应，并报告了更强的酒精奖赏感觉。联合研究的结果表明，如果单独使用药物管理和纳曲酮治疗，87.1%的Asp40携带者有良好的临床结果，而Asn40纯合子只有54.8%。虽然这些发现是有希望的，但研究也强调了等位基因频率不平衡是种族的函数，以至于Asp40等位基因频率在高加索人中约为20%，在非洲血统的人中约为5%，在东亚血统的人中高达50%。因此，该SNP在一定程度上缓和了对NTX的行为和临床反应，必须仔细考虑种族因素，以便将研究结果从主要是高加索人的样本扩展到少数族裔，如亚裔美国人。我们团队的初步工作发现，在东亚血统的人中，Asp40携带者表现出更大的NTX诱导的酒精渴望钝化以及酒精厌恶效应的增强。这项初步研究还发现了对基因剂量反应的支持，即Asp40Asp个体比Asn40Asp基因携带者表现出更大的NTX反应。拟议的新调查员R01试图在这些初步发现的基础上，对东亚裔酗酒者进行三种OPRM1基因型别(Asn40Asn，n=30；Asn40Asp，n=30和Asp40Asp，n=30)的测试。参与者将完成两次双盲、平衡酒精输注和自我给药，一次是在服用NTX(50毫克/天)后，另一次是在服用匹配的安慰剂五天后。在每种用药条件下，参与者将完成一项功能神经成像任务，检查线索诱导的饮酒欲望。这项研究将阐明OPRM1基因Asn40Asp SNP对亚洲血统个体对纳曲酮反应的生物行为和神经标记物的药物遗传效应，亚洲血统是最有可能表达阳性预测等位基因(Asp40)的种族。这项研究的长期目标是优化酒精中毒的药物治疗，并通过推进少数民族群体的药物遗传学研究来解决健康差距。

DESCRIPTION (provided by applicant): Recent pharmacogenetic studies have advanced the gene coding for ¿-opioid receptors (OPRM1) gene as a potential moderator of responses to naltrexone. The most widely studied polymorphism of the OPRM1 gene is the Asn40Asp single nucleotide polymorphism (SNP), a functional mutation thought to affect receptor activity such that the Asp40 variant binds ¿-endorphin three times stronger than the Asn40 allele. Recent studies have found that Asp40 carriers have a stronger striatal dopamine response to intravenous alcohol administration and report stronger feelings of alcohol reward. Findings from the COMBINE Study demonstrated that if treated with Medication Management alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of Asn40 homozygotes. While these findings are promising, studies have also highlighted allele frequency imbalance as a function of ethnicity such that the Asp40 allele frequency is approximately 20% in Caucasians, 5% in individuals of African Ancestry, and as high as 50% among individuals of East Asian descent. Therefore, to the extent to which this SNP moderates behavioral and clinical responses to NTX, ethnicity must be carefully considered in order to extend the findings from primarily Caucasian samples to ethnic minorities, such as Asian Americans. Preliminary work by our team has found that among individuals of East Asian descent, Asp40 carriers show greater NTX-induced blunting of alcohol craving as well as potentiation of the aversive effects of alcohol. This pilot study also found support for a gene dose-response, such that Asp40Asp individuals showed greater NTX responsivity than those with the Asn40Asp genotype. The proposed New Investigator R01 seeks to build upon these preliminary findings by testing heavy drinkers of East Asian descent across three OPRM1 genotypes (Asn40Asn, n = 30; Asn40Asp, n = 30, and Asp40Asp, n = 30). Participants will complete two double-blinded, counterbalanced alcohol infusion and self-administration sessions, one after taking NTX (50 mg/day) and one after taking matched placebo for five days. In each medication condition, participants will complete a functional neuroimaging task examining cue-induced craving for alcohol. This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural markers of response to naltrexone in individuals of Asian descent, an ethnic group most likely to express the positive predictive allele (Asp40). The long-term objective of this research is to optimize alcoholism pharmacotherapy and to address health disparities by advancing pharmacogenetic studies in ethnic minority groups.