Alcohol and benzodiazepine response

LNG的一个策略是测试候选等位基因对抗中间表型，包括酒精反应和苯二氮卓反应，这是易感性的预测。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，并对反应和临床结果进行了心理生理和主观测量；D. Cowley收集了苯二氮卓类药物刺激后敏感而准确的眼球运动测量[使用最初由D. Hommer开发并由现在的LCS代理主任带入西雅图的模式]。到目前为止，我们已经报道了初步的，但积极的结果，LNG发现了一个常见的，非保守的GABAA α 6氨基酸取代，以及P. Lesch [Schuckit等人；Iwata等人]。利用我们在该位点发现的一个新的功能等位基因，对HTTLPR的连锁进行了改进。GABAA α 6基因代表了一个例子，我们已经能够在啮齿动物的基因发现和人类的基因发现之间找到共同点。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，这种取代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差异。人类染色体4和5上的GABAA簇分别与人类[LNG， Long等]和啮齿动物[Portland组]的连锁研究有关。然而，除了大鼠的GABAA α 6结果外，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能够检测到一种常见的非保守氨基酸取代Pro385Ser，并获得与酒精和苯二氮卓类药物敏感性有关的初步证据。酒精反应数据集正在根据M.Schuckit的资源进行扩展，以收集这些个体。我们现在从两个人类分离株获得了GABAA受体在酒精中毒中的作用的趋同数据。利用Chr 5 GABAA基因簇的6位点单倍型，我们检测了芬兰人和西南美洲印第安人酒精中毒的连锁和连锁不平衡。TrimHap （MacLean et al ., 2000）被用于确定影响酒精中毒的基因最可能的位置。在这两个样本中，这个位置都位于alpha6或alpha6及其邻近基因的区域，alpha2亚基是乙醇调节GABAA受体功能所必需的亚基。这项工作最近被扩展为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。先前可用的药物-双硫仑-在ALDH2 Glu487Lys变体中有直接对应物，它可以自然阻断相同的代谢酶。新药，特别是舍曲林和纳曲酮，也可以直接指向分子靶标，这些靶标可能是治疗反应变化的来源，也可能是不同易感程度的来源。两个主要的基因靶点是血清素转运体[舍曲林]和阿片受体[纳曲酮]，其他基因靶点也可以直接推断：HTR1A和HTR1B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神经递质（如多巴胺）功能的各种基因。LNG正致力于对这些基因进行序列变异检测，并发起了一项由S. O'Malley博士领导的重大合作，研究西北印第安部落酗酒者对纳曲酮和舍曲林反应的药物遗传学，以及在COMBINE多中心研究中研究纳曲酮和阿坎prosate的药物遗传学。O'Malley研究的人体研究方案现已得到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mu阿片受体变体，M. Kreek和他的同事已经报道了改变受体对内啡肽的亲和力。这种多态性对表型的影响目前正在大量酗酒者和阿片类药物成瘾者中进行研究。十部落研究。LNG是酒精中毒中基因/环境相互作用的主要代表，包括跨人群研究的使用。十部落研究是一项基因/环境相互作用研究，包括第一个专门用于评估基因/环境相互作用的大型多人口数据集：十部落研究。这项研究大约完成了2/3，收集了来自10个不同美洲印第安部落的300名人口样本的DNA和精神病学访谈[AUDADIS]数据，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.