Multiple polymorphisms in genes of the adrenergic stress system confer vulnerability to alcohol abuse
Multiple polymorphisms in genes of the adrenergic stress system confer vulnerability to alcohol abuse
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DOI：
10.1111/j.1369-1600.2010.00263.x
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发表时间：
2012-01-01
影响因子：
3.4
通讯作者：
Schumann, Gunter
中科院分区：
文献类型：
--
作者：
Clarke, Toni-Kim;Dempster, Emma;Schumann, Gunter
环境因素，如压力，影响酗酒的倾向和发展，以及酗酒复发有显着的影响。对急性应激的一个主要生物反应是去甲肾上腺素的释放，其激活外周应激反应以及下丘脑-垂体-肾上腺轴。我们的目的是研究肾上腺素能系统的两个基因（SLC 6A 2和ADRA 2A）在酒精中毒中的作用，通过对785名成人酒精依赖患者和1237名对照者的21个SNP进行基因分型。SLC 6A 2的两个单核苷酸多态性（SNP）（rs36020和rs36029）与酒精中毒显著相关[错误发现率校正P值（FDR）P = 0.007]。ADRA 2A中的两个SNP（rs 521674和rs602618）与酒精中毒的阳性家族史相关（FDR P = 0.05）。还进行了组合SNP集分析，以确定SLC 6A 2和ADRA 2A中携带多个酒精风险等位基因的风险。Logistic回归分析显示，酒精风险等位基因数量的增加增加了酒精中毒的风险（P = 0.000567，比值比= 1.75，95%置信区间1.262.44）。还发现了由rs 187715、rs36020和rs 40147等位基因组成的三SNP单倍型AGC，与对照组相比，该单倍型在病例中显著过多（61%对56%）。因此，我们证明了SLC 6A 2和ADRA 2A与成人酒精中毒的关联。这些数据证实了肾上腺素能应激系统在考虑酒精依赖遗传易感性时的相关性，并建议应在其他酒精依赖队列中研究SLC 6A 2和ADRA 2A。
Environmental factors such as stress influence both the predisposition to and development of alcoholism, as well as have significant implications for alcoholism relapse. One predominant biological response to acute stress is the release of norepinephrine, which activates the peripheral stress response and also the hypothalamicpituitaryadrenal axis. We aimed to examine the role of two genes of the adrenergic system (SLC6A2 and ADRA2A) in alcoholism by genotyping 21 SNPs in 785 adult alcohol-dependent patients and 1237 controls. Two single nucleotide polymorphisms (SNP) (rs36020 and rs36029) in SLC6A2 were significantly associated with alcoholism [false discovery rate corrected P-value (FDR) P = 0.007]. Two SNPs in ADRA2A (rs521674 and rs602618) were associated with a positive family history of alcoholism (FDR P = 0.05). A combined SNP-set analysis was also carried out to determine the risk of harbouring multiple alcohol risk alleles across SLC6A2 and ADRA2A. Logistic regression analysis revealed that an increase in the number of alcohol risk alleles increased the risk for alcoholism (P = 0.000567, odds ratio = 1.75, 95% confidence interval 1.262.44). A three-SNP haplotype consisting of rs187715, rs36020 and rs40147 alleles, AGC, was also found, which was significantly over-represented in cases compared with controls (61% versus 56%). We therefore demonstrate an association of SLC6A2 and ADRA2A with adult alcoholism. These data confirm the relevance of the adrenergic stress system when considering genetic predisposition to alcohol dependence and suggest that SLC6A2 and ADRA2A should be studied in additional alcohol-dependent cohorts.