Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study
Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study
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DOI：
10.1111/j.1360-0443.2008.02236.x
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发表时间：
2008-06-01
期刊：
影响因子：
6
通讯作者：
Madden, Pamela A. F.
中科院分区：
文献类型：
--
作者：
Agrawal, Arpana;Pergadia, Michele L.;Madden, Pamela A. F.
目的γ-氨基丁酸受体A（GABRA）基因簇4号和5号染色体上已检查其与酒精和药物依赖表型。令人信服的证据表明，GABRA 2与酒精和药物依赖有关。然而，没有研究调查GABA（A）基因簇中的基因是否与尼古丁依赖相关，尼古丁依赖是一种与持续吸烟高度相关的重要表型，是全球唯一最可预防的死亡原因。设计使用1050例尼古丁依赖病例和879例非依赖性吸烟对照的数据，我们使用逻辑回归来检查GABAA受体系统中13个基因以及GABBR 2（GABA（B）基因）中单核苷酸多态性（SNP）之间的关联。结果：我们发现证据表明GABRA 4中的四个SNP，GABRA 2中的两个SNP和GABRE中的一个SNP与尼古丁依赖之间存在关联。这些包括GABRA 2（rs 279858）的同义多态性，位于高度保守的区域，以前已被证明与酒精和药物依赖有关。GABRA 4的一个非同义多态性（rs 16859834/rs 2229940）也是高度保守的，P值为0.03。发现与尼古丁依赖相关的显著单倍型为GABRA 2。未观察到上位相互作用的证据。我们的研究没有发现GABBR 2基因与尼古丁依赖之间存在关联的证据。结论：考虑到化合物在戒烟研究中增强GABA能神经传递的潜在作用，这些发现对更广泛的成瘾研究领域具有巨大的潜力。
Aims The gamma-aminobutyric acid receptor A (GABRA) gene clusters on chromosomes 4 and 5 have been examined previously for their association with alcohol and drug dependence phenotypes. Compelling evidence suggests that GABRA2 is associated with alcohol and drug dependence. However, no study has investigated whether genes in the GABA(A) gene clusters are associated with nicotine dependence, an important phenotype with a high correlation to persistent smoking, the single most preventable cause of mortality world-wide. Design Using data on 1050 nicotine-dependent cases and 879 non-dependent smoking controls, we used logistic regression to examine the association between single nucleotide polymorphisms (SNPs) in 13 genes in the GABAA receptor system as well as GABBR2 (a GABA(B) gene). Findings We found evidence for association between four SNPs in GABRA4, two SNPs in GABRA2 and one SNP in GABRE with nicotine dependence. These included a synonymous polymorphism in GABRA2 (rs279858), lying in a highly conserved region, which has been shown previously to be associated with alcohol and drug dependence. A non-synonymous polymorphism (rs16859834/rs2229940) in GABRA4, also highly conserved, was associated at P-value of 0.03. Significant haplotypes associated with nicotine dependence were found for GABRA2. No evidence for epistatic interactions were noted. Our study did not find evidence for an association between GABBR2 gene and nicotine dependence. Conclusions Given the potential role of compounds that enhance GABAergic neurotransmission in smoking cessation research, these findings have enormous potential for informing the wider field of addiction research.