Significant Association of ANKK1 and Detection of a Functional Polymorphism with Nicotine Dependence in an African-American Sample
Significant Association of ANKK1 and Detection of a Functional Polymorphism with Nicotine Dependence in an African-American Sample
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DOI：
10.1038/npp.2008.37
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发表时间：
2009-01-01
影响因子：
7.6
通讯作者：
Li, Ming D.
中科院分区：
文献类型：
--
作者：
Huang, Weihua;Payne, Thomas J.;Li, Ming D.
大脑中的多巴胺能系统在尼古丁成瘾中起着关键作用。多巴胺能系统中的遗传变异，包括多巴胺受体基因中的遗传变异，代表了尼古丁依赖（ND）遗传研究的可能候选者。我们研究了多巴胺D-2受体基因（DRD 2）及其邻近的锚蛋白重复序列和激酶结构域1基因（ANKK 1）的各种多态性，以确定它们是否与ND相关。我们在中南烟草家族队列中检测了DRD 2的16个单核苷酸多态性（SNP）和ANKK 1的7个SNP，该队列由代表两个不同美国人群的2037名参与者组成。DRD 2中的几个SNPs（rs7131056、rs 4274224、rs 4648318和rs6278），沿着ANKK 1中的Taq IA多态性（rs 1800497），揭示了在欧洲裔美国人中与ND的初始显著关联，但在多次测试校正后没有，表明DRD 2与ND的弱关联。相比之下，ANKK 1与非裔美国人和合并样本中ND的关联，特别是SNP rs 2734849，在校正后仍然显着。rs 2734849通过非同义的G到A转换，在ANKK 1的C-末端锚蛋白重复结构域中产生氨基酸变化（精氨酸到组氨酸）。使用荧光素酶报告基因分析，我们进一步证明了该变体改变了NF-κ B调控基因的表达水平。由于DRD 2的表达受转录因子NF-κ B B的调节，我们怀疑rs 2734849可能间接影响多巴胺D2受体密度。我们的结论是，ANKK 1与ND和多态性rs 2734849 ANKK 1代表了一个功能性的致病变异的ND在非洲裔美国人吸烟者。
The dopaminergic system in the brain plays a critical role in nicotine addiction. Genetic variants in the dopaminergic system, including those in dopamine receptor genes, represent plausible candidates for the genetic study of nicotine dependence (ND). We investigated various polymorphisms in the dopamine D-2 receptor gene (DRD2) and its neighboring ankyrin repeats and kinase domain containing 1 gene (ANKK1) to determine whether they were associated with ND. We examined 16 single nucleotide polymorphisms ( SNPs) at DRD2 and 7 SNPs at ANKK1 in our Mid-South Tobacco Family cohort, which consisted of 2037 participants representing two distinct American populations. Several SNPs (rs7131056, rs4274224, rs4648318, and rs6278) in DRD2, along with the Taq IA polymorphism (rs1800497) in ANKK1, revealed initial significant associations with ND in European Americans, but not after correction for multiple testing, indicating a weak association of DRD2 with ND. In contrast, associations for ANKK1 with ND in the African-American and pooled samples, specifically for SNP rs2734849, remained significant after correction. With a non-synonymous G to A transition, rs2734849 produces an amino-acid change ( arginine to histidine) in C-terminal ankyrin repeat domain of ANKK1. Using the luciferase reporter assay, we further demonstrated that the variant alters expression level of NF-kappa B-regulated genes. Since DRD2 expression is regulated by transcription factor NF-kappa B, we suspect that rs2734849 may indirectly affect dopamine D2 receptor density. We conclude that ANKK1 is associated with ND and polymorphism rs2734849 in ANKK1 represents a functional causative variant for ND in African-American smokers.