Huang Weihua, Ma Jennie Z, Payne Thomas J, Beuten Joke, Dupont Randolph T, Li Ming D
Department of Psychiatry and Neurobehavioral Sciences, Section of Neurobiology, University of Virginia, 1670 Discovery Drive, Suite 125, Charlottesville, VA 22911, USA.
Hum Genet. 2008 Mar;123(2):133-40. doi: 10.1007/s00439-007-0453-9. Epub 2007 Dec 19.
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 Fagerström 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.
流行病学研究有力地表明基因与吸烟行为有关。多巴胺能系统中的基因介导了尼古丁的强化和致依赖特性，是尼古丁依赖（ND）相关作用的可能候选基因。在本研究中，我们检测了多巴胺D(1)受体基因（DRD1）内部或附近的五个单核苷酸多态性（SNP）与ND的关联，ND通过吸烟量（SQ）、吸烟严重程度指数（HSI）和尼古丁依赖的法格斯特罗姆测试（FTND）进行评估。样本来自2037名参与者，代表200个欧裔美国人（EA）家庭和402个非裔美国人（AA）家庭。尽管我们在AA样本中发现SNP rs265973、rs686和rs4532；在EA样本中发现rs4532；在合并样本中发现rs265975、rs686和rs4532与各种ND指标存在显著关联，但在多重检验校正后，只有AA样本中的rs686以及合并样本中的rs686和rs4532的关联仍具有显著性。基于单倍型的关联分析显示，由rs265973、rs265975和rs686组成的单倍型C-T-A在AA样本和合并样本中均与所有三个ND指标显著相关。另一个由rs265975、rs686和rs4532组成的单倍型T-A-T在合并样本中与FTND显著相关。此外，在荧光素酶报告基因检测中，位于3'非翻译区的rs686导致了荧光素酶活性的差异，表明rs686是一个影响DRD1表达的功能性多态性位点。
