Variants in nicotinic receptors and risk for nicotine dependence
Variants in nicotinic receptors and risk for nicotine dependence
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DOI：
10.1176/appi.ajp.2008.07111711
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发表时间：
2008-09-01
影响因子：
17.7
通讯作者：
Goate, Alison M.
中科院分区：
文献类型：
--
作者：
Bierut, Laura Jean;Stitzel, Jerry A.;Goate, Alison M.
目的：最近的一项研究暂时确定了许多遗传变异作为从吸烟过渡到尼古丁依赖发展的风险因素，包括α 5烟碱胆碱能受体（CHRNA5）中的氨基酸变化。本研究的目的是复制这些研究结果在一个独立的数据集，更彻底地调查的作用，遗传变异的集群物理连接的烟碱受体，CHRNA5-CHRNA3-CHRNB4，和吸烟的风险。方法：个人从219个欧洲美国家庭（N = 2,284）基因分型在这个基因簇，以测试与吸烟的遗传关联。在来自不同种族人群的995个个体中研究了氨基酸变体（rs16969968）的频率。在体外研究中进行直接测试是否在CHRNA5的氨基酸变异影响receptor functions.Results：标记的氨基酸变化的遗传变异显示与吸烟表型（p = 0.007）。这种变异在非人类物种中处于高度保守的区域内，但其频率在不同人群中存在差异（非洲人群中为0%，欧洲人群中为37%）。此外，功能研究表明，风险等位基因降低尼古丁激动剂的反应。第二个独立发现见于rs578776（p = 0.003），这种关联的功能意义尚不清楚。结论：这项研究证实，在这个烟碱受体基因簇中至少有两个独立的变异体有助于某些人群习惯性吸烟的发展，它强调了多种遗传变异对不同人群常见疾病发展的重要性。
Objective: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the alpha 5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking.Method: Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function.Results: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown.Conclusions: This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.