Alcohol and benzodiazepine response

酒精和苯二氮卓类药物的反应

• 批准号: 6983154
• 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/6983154
• 关键词: GABA receptor; alcoholism /alcohol abuse chemotherapy; behavioral /social science research tag; behavioral genetics; benzodiazepines; clinical research; disulfiram; drug screening /evaluation; gene environment interaction; genetic polymorphism; human data; human genetic material tag; human subject; naltrexone; opioid receptor; pharmacogenetics; serotonin transporter; sertraline

A strategy of LNG is to test candidate alleles against intermediate phenotypes including alcohol response and benzodiazepine response, which are predictive of vulnerability. Datasets for these two intermediate phenotypes have been developed in collaboration with their acknowledged experts: M. Schuckit who has prospectively followed a cohort of 450 men and has available psychophysiological and subjective measures of response as well as clinical outcome, and D. Cowley, who had collected sensitive and accurate eye-movement measures following benzodiazepine challenge [using the paradigm originally developed and brought to Seattle by D. Hommer, now Acting Chief of LCS]. Thus far we have reported preliminary, but positive results with a common, non-conservative GABAA alpha6 amino acid substitution discovered by LNG as well as with the functional serotonin transporter polymorphism HTTLPR described by P. Lesch [Schuckit et al; Iwata et al]. The linkage to HTTLPR was improved by use of a new functional allele we discovered at this locus. The GABAA alpha6 gene represents an example of where we have been able to find convergence between a rodent genetic finding and the human. Korpi et al detected a GABAA alpha6 amino acid substitution altering the sensitivity of this receptor to alcohol and benzodiazepines and this substitution predicts the difference in alcohol sensitivity observed between alcohol accepting and non-accepting Finnish rats. The GABAA clusters on human chromosomes 4 and 5 are implicated by linkage studies in the human [LNG, Long et al] and in the rodent [Portland group], respectively. Nevertheless, except for the GABAA alpha6 result in the rat, alpha6 might not have been the first GABAA receptor we evaluated in the human because the GABAA alpha6 is restricted in its expression to cerebellum. As discussed above, LNG was able to detect a common, non-conservative amino acid substitution Pro385Ser and obtain preliminary evidence for involvement in alcohol and benzodiazepine sensitivity The alcohol response dataset is being expanded according to M.Schuckit's resources to collect these individuals. We now have convergent data from two human isolates for a role for GABAA receptors in alcoholism. Using a six-locus haplotype for the Chr 5 GABAA gene cluster, we detected linkage and linkage disequilibrium in alcoholism in both Finns and SW American Indians. TrimHap (MacLean et al, 2000) was used to establish the most likely location of a gene influencing alcoholism. In both samples, this location was in the alpha6 or in the region of alpha6 and the adjacent gene for the alpha2 subunit, a subunit which is necessary for modulation of GABAA receptor function by ethanol. This work has recently been expanded with multi-locus dense SNP maps for both the chr 5 cluster and chr 4 clusters. Pharmacogenetics of treatment response. A radical change in alcoholism research is that several pharmacological treatments have recently become available that improve the ability of alcoholics to maintain abstinence. The previously available drug - disulfiram - had a direct counterpart in the ALDH2 Glu487Lys variant which created a natural blockade of the same metabolic enzyme. The new drugs, particularly sertraline and naltrexone, could also point directly to molecular targets which could be either sources of variation in treatment response or sources of differential vulnerability. Two principal gene targets are the serotonin transporter [sertraline] and the m opioid receptor [naltrexone], and other gene targets are also directly inferred: HTR1A and HTR1B autoreceptors, postsynaptic serotonin receptors, opioid propeptides, and various genes involved in the function of interacting neurotransmitters such as dopamine. LNG is focusing efforts in sequence variant detection towards these genes and by initiating a major collaboration led by Dr. S. O'Malley towards the pharmacogenetics of naltrexone and sertralinne response among alcoholics in a NW Indian tribe and towards the pharmacogenetics of naltrexone and acamprosate in the COMBINE multicenter study. The human research protocol for the O'Malley study is now approved by the NIAAA IRB and this study is underway. LNG's molecular studies have already yielded a common, nonconservative mu opioid receptor variant which M. Kreek and colleagues have reported alters affinity of the receptor for endomorphin. Effect of this polylmorphism on phenotype is now being studied in large cohorts of alcoholics and opioid addicts. Ten Tribes Study. LNG is a leading exponent of gene/environment interactions in alcoholism, including the use of cross-population studies. The Ten Tribes Study is a gene/environment interaction study encompassing the collection of the first large multi-population dataset specifically suited for evaluation of gene/environment interaction: the Ten Tribes Study. This study, which is approximately 2/3 complete involves the collection of DNA and psychiatric interview [AUDADIS] data on 300 demographically sampled individuals from 10 different American Indian tribes, including tribes with widely disparate rates of alcoholism and alcohol associated problems. This dataset will be used to study the effects of social and historical determinants on alcoholism, effects of alcoholism on communities [especially rates and types of trauma], and interaction of genetic factors with environmental loadings and thresholds.

液化天然气的一种策略是针对包括酒精反应和苯二氮卓反应在内的中间表型测试候选等位基因，这些反应可预测脆弱性。 Datasets for these two intermediate phenotypes have been developed in collaboration with their acknowledged experts: M. Schuckit who has prospectively followed a cohort of 450 men and has available psychophysiological and subjective measures of response as well as clinical outcome, and D. Cowley, who had collected sensitive and accurate eye-movement measures following benzodiazepine challenge [using the paradigm originally developed and brought to Seattle by D. Hommer, now LCS代理主任]。到目前为止，我们已经报道了液化天然气和功能性5-羟色胺转运蛋白多态性HTTLPR所描述的常见的，非保守的GABAA Alpha6氨基酸取代的初步结果。 Iwata等人]。通过使用我们在此基因座发现的新功能等位基因，可以改善与HTTLPR的联系。 GABAAα6基因代表了我们能够在啮齿动物遗传发现与人之间找到收敛性的一个例子。 Korpi等人检测到GABAA Alpha6氨基酸的取代，从而改变了该受体对酒精和苯二氮卓类药物的敏感性，而这种替代物可以预测酒精接受和非接受芬兰大鼠的酒精敏感性差异。人类染色体4和5的GABAA簇分别与人类[LNG，Long等]和啮齿动物[Portland Group]的连锁研究有关。然而，除了gabaa alpha6导致大鼠外，α6可能不是我们在人类中评估的第一个GABAA受体，因为GABAA alpha6的表达限制为小脑。如上所述，LNG能够检测出常见的非保守氨基酸取代Pro385ser，并获得了参与酒精和苯二氮卓类敏感性的初步证据，该酒精反应数据集正在扩大，该数据集得到了扩展。现在，我们从两个人类分离株中收集了收敛数据，以在酒精中毒中发挥GABAA受体的作用。我们使用六级单位单倍型用于CHR 5 GABAA基因簇，我们检测到芬兰和SW美洲印第安人的酒精中毒的连锁和连锁不平衡。 Trimhap（MacLean等，2000）用于建立影响酒精中毒的基因的最可能位置。在这两个样品中，该位置均位于alpha6或alpha6区域和alpha2亚基的相邻基因，这是一种亚基，这是乙醇调节GABAA受体功能所必需的亚基。最近，对于CHR 5群集和CHR 4簇的多层密度SNP地图，这项工作已扩展。治疗反应的药物遗传学。酒精中毒研究的根本性变化是，最近已经获得了几种药理治疗，以提高酒精中毒的能力维持戒酒。先前可用的药物-Disulfiram-在ALDH2 GLU487LYS变体中具有直接的对应物，该变体造成了同一代谢酶的自然封锁。新药，尤其是舍曲林和纳曲酮，也可以直接指向分子靶标，这些靶标可能是治疗反应的差异或差异脆弱性来源的来源。 Two principal gene targets are the serotonin transporter [sertraline] and the m opioid receptor [naltrexone], and other gene targets are also directly inferred: HTR1A and HTR1B autoreceptors, postsynaptic serotonin receptors, opioid propeptides, and various genes involved in the function of interacting neurotransmitters such as dopamine.液化天然气正在将重点放在对这些基因的序列变体中，并通过S. O'Malley博士领导的主要合作促进了NW印度部落中酒精中毒的药物遗传学和Sertralinne的药物遗传学，以及在组合中纳尔特雷酮和辅助剂的药物遗传学中，在组合型多中心研究中。 O'Malley研究的人类研究方案现已获得NIAAA IRB的批准，这项研究正在进行中。 LNG的分子研究已经产生了一种常见的非保守MU阿片受体变体，M。Kreek及其同事报告了该受体对内派代寄生的亲和力的变化。现在，正在研究大量酗酒者和阿片类药物成瘾者，这种多态性对表型的影响。十个部落研究。液化天然气是酒精中毒基因/环境相互作用的主要指数，包括使用交叉人群研究。十个部落的研究是一项基因/环境相互作用研究，其中包括专门用于评估基因/环境相互作用的第一个大型多人群数据集的收集：十个部落研究。这项研究约为2/3，涉及收集来自10个不同美洲印第安人部落的300个人口统计学抽样个体的DNA和精神访谈[Audadis]数据，其中包括与酒精中毒和酒精相关的问题的分散率。该数据集将用于研究社会和历史决定因素对酒精中毒的影响，酒精中毒对社区的影响（尤其是创伤的比率和类型）以及遗传因素与环境负荷和阈值的相互作用。