Alcohol and benzodiazepine response

LNG的一个策略是针对中间表型测试候选等位基因，包括酒精反应和苯二氮卓类反应，这是脆弱性的预测。这两种中间表型的数据集是与他们公认的专家合作开发的：M。Schuckit对450名男性进行了前瞻性随访，并对心理生理和主观反应以及临床结果进行了测量。Cowley，他收集了苯二氮卓类药物激发后敏感而准确的眼动测量数据[使用最初由D。侯默，现为LCS代理主任。到目前为止，我们已经报告了初步的阳性结果，LNG发现了常见的非保守性GABAA α 6氨基酸取代以及P. Lesch描述的功能性5-羟色胺转运蛋白多态性HTTLPR [Schuckit et al;岩田et al]。通过使用我们在该位点发现的一个新的功能等位基因，与HTTLPR的连锁得到改善。GABAA α 6基因代表了一个例子，我们已经能够找到啮齿动物遗传发现和人类之间的趋同。Korpi等人检测到GABAA α 6氨基酸取代改变了该受体对酒精和苯二氮卓类药物的敏感性，该取代预测了在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差异。人4号和5号染色体上的GABAA簇分别与人[LNG，Long et al]和啮齿动物[波特兰组]中的连锁研究有关。然而，除了大鼠中的GABAA α 6结果之外，α 6可能不是我们在人类中评估的第一个GABAA受体，因为GABAA α 6的表达仅限于小脑。如上所述，LNG能够检测到常见的非保守氨基酸取代Pro385 Ser，并获得参与酒精和苯二氮卓类药物敏感性的初步证据。我们现在有收敛的数据从两个人类分离的作用，GABAA受体在酒精中毒。使用六个位点的单倍型的Chr 5 GABAA基因簇，我们发现在芬兰人和西南美洲印第安人的酒精中毒的连锁和连锁不平衡。TrimHap（MacLean et al，2000）用于确定影响酒精中毒的基因的最可能位置。在这两个样品中，该位置位于α 6或α 6和α 2亚基的相邻基因区域中，α 2亚基是乙醇调节GABAA受体功能所必需的亚基。这项工作最近已扩大与多位点的密集SNP图谱的chr 5集群和chr 4集群。治疗反应的药物遗传学。酒精中毒研究的一个根本变化是，最近出现了几种药物治疗方法，可以提高酗酒者保持戒酒的能力。以前可用的药物-双硫仑-在ALDH 2 Glu 487 Lys变体中具有直接对应物，其产生了对相同代谢酶的天然阻断。新药，特别是舍曲林和纳曲酮，也可以直接指向分子靶点，这些分子靶点可能是治疗反应变化的来源，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[纳洛酮]，其他基因靶点也被直接推断：HTR 1A和HTR 1B自身受体，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如多巴胺功能的各种基因。液化天然气是集中努力在序列变异检测对这些基因，并启动了一个重大的合作，由博士S。O 'Malley对西北印第安部落酗酒者中纳曲酮和舍曲林反应的药物遗传学以及对联合收割机多中心研究中纳曲酮和阿坎酸的药物遗传学的研究。O 'Malley研究的人类研究方案现已获得NIAAA IRB的批准，该研究正在进行中。LNG的分子研究已经产生了一种常见的、非保守的μ阿片受体变异体，Kreek及其同事报道了内吗啡肽受体亲和力的改变。这种多态性对表型的影响目前正在大量的酗酒者和阿片类药物成瘾者中进行研究。十大部落研究。LNG是酒精中毒中基因/环境相互作用的主要代表，包括使用交叉人群研究。十大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用于评估基因/环境相互作用的大型多人群数据集：十大部落研究。这项研究大约完成了2/3，涉及收集来自10个不同美洲印第安部落的300名人口统计学抽样个体的DNA和精神病学访谈[AUDADIS]数据，其中包括酗酒率和酒精相关问题差异很大的部落。该数据集将用于研究社会和历史决定因素对酗酒的影响，酗酒对社区的影响[特别是创伤的发生率和类型]，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.