GENETICS OF NICOTINE DEPENDENCE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。吸烟是一种非常普遍和有害的行为。每年，吸烟导致全球约300万人死亡，仅在美国就估计有43.5万人死亡。超过98%的烟草吸烟者是烟民。尽管少数吸烟者不每天吸烟，但大多数人每天吸烟，并在身体上依赖尼古丁，尼古丁是香烟烟雾的主要成瘾成分。像所有的物质依赖障碍一样，尼古丁依赖也有很大的可遗传成分。在过去的几十年里，许多大样本的双胞胎研究得出结论，遗传因素导致了成为经常吸烟的人的风险。多巴脱羧酶(DDC；又称L氨基酸脱羧酶；AADC)参与多巴胺、去甲肾上腺素和5-羟色胺的合成。由于中脑边缘多巴胺能系统参与包括尼古丁在内的许多药物的强化作用，DDC基因被认为是参与尼古丁依赖易感性(ND)发生的可能候选基因。在对602个非洲或欧洲裔美国人血统的核心家庭的研究中，我们发现了DDC参与ND易感性的证据，以及其影响的种族特异性。我们还测试了烟碱型乙酰胆碱受体α4亚单位基因(CHRNA4)中的6个单核苷酸多态(SNPs)和β2亚基基因(CHRNB2)中的4个单核苷酸多态(SNPs)，发现了令人信服的证据表明nAChRα4亚单位参与尼古丁成瘾，而nAChRβ2亚单位没有参与尼古丁成瘾。最后，我们发现神经营养酪氨酸激酶受体2基因的特定单倍型与尼古丁依赖的易感性有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cigarette smoking is a highly prevalent and harmful behavior. Annually, tobacoo smoking is responsible for approximately three million deaths world-wide, with an estimated 435,000 deaths in the USA alone. More than 98% of tobacoo users are cigarette smokers. Although a minority of tobacco smokers do not smoke daily, most do and are physically dependent on nicotine, the primary addictive component of cigarette smoke. Like all substance-dependence disorders, nicotine dependence has a substantial heritable component. Over the last few decades, many large-sample twin studies have concluded that genetics contributes to the risk of becoming a regualr smoker. DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). In a study of 602 nuclear families of African- or European-American ancestry, we found evidence for the involvement of DDC in the susceptibility to ND and, further, racial specificity of its impact. We also tested six single nucleotide polymorphisms (SNPs) in the alpha 4 subunit gene (CHRNA4) and four SNPs in the beta 2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors for association with nicotine dependence, and found convincing evidence for the involvement of the nAChR alpha 4 subunit, but not of the nAChR beta 2 subunit, in nicotine addiction. Finally, we found association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene with vulnerability to nicotine dependence.