Alcohol and benzodiazepine response

液化天然气的一个策略是测试候选等位基因与包括酒精反应和苯二氮卓类反应在内的中间表型，这些中间表型可以预测易损性。这两个中间表型的数据集是与他们公认的专家合作开发的：M.Schuckit，他前瞻性地跟踪了450名男性的队列，并且有可用的心理生理学和主观反应指标以及临床结果；D.Cowley，他在苯二氮卓类药物挑战之后收集了敏感和准确的眼球运动测量数据[使用的是D.Hommer最初开发并带到西雅图的范式，他现在是LCS的代理局长]。到目前为止，我们已经报告了LNG发现的常见的、非保守的GABAAα6氨基酸替代以及P.Lesch描述的功能性5-羟色胺转运体多态HTTLPR的初步但积极的结果[Schuckit等人；Iwata等人]。利用我们在该基因座上发现的一个新的功能等位基因，改善了与HTTLPR的连锁。GABAA alpha6基因代表了我们能够在啮齿动物基因发现和人类之间找到趋同的一个例子。Korpi等人检测到GABAAα6氨基酸替换改变了该受体对酒精和苯二氮类药物的敏感性，这种替换预测了接受酒精和不接受酒精的芬兰大鼠之间观察到的酒精敏感性的差异。人类染色体4和5上的GABAA簇分别与人类[LNG，Long等人]和啮齿动物[波特兰组]的连锁研究有关。然而，除了大鼠的GABAAα6结果外，α6可能不是我们在人类中评估的第一个GABAA受体，因为GABAAα6的表达仅限于小脑。如上所述，LNG能够检测到一种常见的、非保守的氨基酸替代Pro385Ser，并获得了参与酒精和苯二氮卓类敏感性的初步证据。我们现在有了来自两个人类分离株的关于GABAA受体在酒精中毒中的作用的一致数据。利用Chr 5 GABAA基因簇的6个位点的单倍型，我们在芬兰人和西南部美洲印第安人中都发现了酒精中毒的连锁和连锁不平衡。TrimHap(MacLean等人，2000)被用来确定影响酒精中毒的基因的最可能的位置。在这两个样本中，这个位置都在α6或α6和α2亚单位的相邻基因区域，α2亚单位是乙醇调节GABAA受体功能所必需的一个亚单位。最近，这项工作得到了扩展，得到了Chr 5簇和Chr 4簇的多位点密集SNP图谱。治疗反应的药物遗传学。酒精中毒研究的一个根本性变化是，最近出现了几种药物治疗方法，可以提高酗酒者维持戒酒的能力。以前可用的药物-双硫兰-在ALDH2 Glu487Lys变体中有一个直接的对应物，它会自然地阻断相同的代谢酶。新药，特别是舍曲林和纳曲酮，也可以直接指向分子靶点，这些靶点可能是治疗反应的变异来源，也可能是不同脆弱性的来源。两个主要的基因靶点是5-羟色胺转运体[舍曲林]和m阿片受体[纳曲酮]，其他基因靶点也被直接推断：HTR1A和HTR1B自体受体，突触后5-羟色胺受体，阿片前肽，以及参与相互作用的神经递质功能的各种基因，如多巴胺。LNG公司正致力于针对这些基因进行序列变异检测，并通过启动S.O‘Malley博士领导的一项重大合作，在西北印第安人部落的酗酒者中开展纳曲酮和舍曲林反应的药物遗传学研究，并在联合多中心研究中开展纳曲酮和氨基己酸酯的药物遗传学研究。O‘Malley研究的人体研究方案现已获得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、非保守的u阿片受体变体，M.Kreek和他的同事报告说，这种变体改变了内吗啡受体的亲和力。这种多态对表型的影响目前正在大量酗酒者和阿片成瘾者中进行研究。十大部落研究。液化天然气是酒精中毒中基因/环境相互作用的主要指标，包括跨人群研究的使用。十个部落研究是一项基因/环境相互作用研究，包括收集第一个专门适用于评估基因/环境相互作用的大型多种群数据集：十个部落研究。这项研究大约完成了三分之二，收集了来自10个不同美洲印第安人部落的300名人口样本个人的DNA和精神病学访谈[AUDADIS]数据，其中包括酗酒和酒精相关问题发生率差异很大的部落。这个数据集将被用来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[特别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。

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.