PNAS：揭示酒瘾遗传学机制
最近，弗吉尼亚州立联邦大学(VCU)医学院的科研人员，发现了一个生物学线索，可以帮助解释“为什么有些人对酒精成瘾而其他人则不”。
这些结果，可使研究人员更容易提早发现那些处于酒精成瘾风险的人，并设计更有效的药物治疗方法，来帮助人们戒酒。
根据美国国家卫生统计机构显示，在美国大约有1800万人滥用酒精。绝大多数得不到治疗。
VCU医学院药理学和毒理学系副教授Jill C. Bettinger博士说：“帮助人们戒酒的药物治疗很少，而且不够完善，因为这是一个非常困难的人类遗传学问题。如果我们可以更好地理解酒精的分子作用，我们就可以设计更合理的治疗方法，甚至提醒哪些人更容易患上酒瘾。”
相关研究结果以“SWI/SNF Chromatin Remodeling Regulates Alcohol Response Behaviors in Caenorhabditis Elegans and is Associated With Alcohol Dependence in Humans”为题发表在最近的《美国国家科学院院刊》(PNAS)，Bettinger是论文的资深作者。
在这项研究中，研究人员检测了一个蛋白质复合体——称为switching defective/sucrose nonfermenting(SWI/SNF)对决定线虫对酒精的行为反应所起的作用。
通过显微镜，研究人员观察到，线虫开始饮酒，并且，根据哪些基因在SWI/SNF复合中表达，线虫对酒精的初始敏感性和耐受性发生了变化。
因为人类和蠕虫有相似的基因组成，所以Bettinger求助于本文共同作者、VCU医学院精神病学和人类分子遗传学系副教授Brien P. Riley博士。Riley是弗吉尼亚精神和行为遗传学研究所分子遗传学实验室主任，那里的研究人员一直致力于研究人类基因组及其与疾病或其他性状之间的关系。
Riley发现，在相同SWI/SNF复合体中自然发生的、对线虫耐受性至关重要的遗传变化，也与人类的酒精依赖相关。不像亨廷顿和其他疾病，可以关联到一个单基因的突变，有证据表明，发展酗酒的可能性是多基因突变的产物，每个突变都产生小的影响。SWI/SNF复合体基因是其中的一块拼图。
研究结果也为研究人员提供了一个完美的模型，以继续进行他们的研究。
Riley 说：“在诸如线虫这样的模型系统中鉴定对耐受性发展至关重要的基因，将推动我们对人类酒精依赖性的理解。如果在线虫中看到同样的效果，那么我们就能形成并检测关于‘什么种类的变化会导致人类酒精依赖的风险增加’的功能假说。”
Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematodeCaenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.
作者：Laura D. Mathies
