Significant association of DRD1 with nicotine dependence
Significant association of DRD1 with nicotine dependence
复制标题
DOI：
10.1007/s00439-007-0453-9
复制
发表时间：
2008-03-01
期刊：
影响因子：
5.3
通讯作者：
Li, Ming D.
中科院分区：
文献类型：
--
作者：
Huang, Weihua;Ma, Jennie Z.;Li, Ming D.
流行病学研究强烈暗示吸烟行为与遗传有关。多巴胺能系统中的基因介导尼古丁的增强和产生依赖性，是尼古丁依赖（ND）中可能的候选基因。在这项研究中，我们研究了多巴胺D-1受体基因（DRD 1）内或附近的5个单核苷酸多态性（SNPs）与ND的关联，通过吸烟量（SQ），吸烟指数（HSI）和Fagerstrom ND试验（FTND）进行评估。样本来自2,037名参与者，代表200个欧洲裔美国人（EA）和402个非洲裔美国人（AA）家庭。虽然我们发现在AA样本中，rs 265973、rs686和rs 4532的SNPs显著相关，但在EA样本中，rs 4532的SNPs显著相关。以及rs 265975、rs686和rs 4532在具有各种ND测量的合并样品中的分布，在多重检验校正后，只有AA样品中的rs686和合并样品中的rs686和rs 4532的相关性仍然显著。基于单倍型的关联分析显示，由rs 265973、rs 265975和rs686形成的单倍型C-T-A与AA和合并样本中的所有三种ND指标显著相关。另一种单倍型T-A-T由rs 265975、rs686和rs 4532形成，在合并样本中显示与FTND显著相关。此外，在荧光素酶报告基因测定中，位于3'非翻译区的rs686引起差异荧光素酶活性，表明rs686是影响DRD 1表达的功能多态性。
Epidemiologic studies have strongly implicated genetics in smoking behavior. Genes in the dopaminergic system, which mediates the reinforcing and dependence-producing properties of nicotine, are plausible candidates for roles in nicotine dependence (ND). In this study, we examined five single-nucleotide polymorphisms (SNPs) within or near the dopamine D-1 receptor gene (DRD1) for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). The samples were obtained from 2,037 participants representing 200 European American (EA) and 402 African American (AA) families. Although we found significant associations of SNPs rs265973, rs686, and rs4532 in the AA sample; of rs4532 in the EA sample; and of rs265975, rs686, and rs4532 in the pooled sample with various ND measures, only the association of rs686 in the AA sample and of rs686 and rs4532 in the pooled sample remained significant after correction for multiple testing. Haplotype-based association analysis revealed that haplotype C-T-A, formed by rs265973, rs265975, and rs686, was significantly associated with all three ND measures in both the AA and the pooled sample. Another haplotype, T-A-T, formed by rs265975, rs686, and rs4532, showed a significant association with FTND in the pooled sample. Furthermore, in a luciferase reporter assay, rs686, located in the 3' untranslated region, caused differential luciferase activities, indicating that rs686 is a functional polymorphism affecting expression of DRD1.