Ait-Daoud Nassima, Seneviratne Chamindi, Smith Justin B, Roache John D, Dawes Michael A, Liu Lei, Wang Xin-Qun, Johnson Bankole A
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia Charlottesville, VA, USA.
Front Psychiatry. 2012 Feb 16;3:6. doi: 10.3389/fpsyt.2012.00006. eCollection 2012.
We previously have shown that cue-induced alcohol craving and propensity for higher drinking are modulated by allelic differences in SLC6A4 associated with serotonin transporter (5-HTT) expression level alterations. In an independent study, we characterized another polymorphism, SNP rs1042173, in 3'-untranslated region (3'-UTR) of the same gene, which also altered 5-HTT expression levels; the T allele of rs1042173 was associated with lower mRNA and protein levels. In subsequent analyses, the TT genotype was found to be associated with higher drinking intensity in alcohol-dependent (AD) individuals of Caucasian descent. Building upon these findings, we hypothesized that the low-expressing TT genotype associated with intense drinking would predict higher craving for alcohol in AD individuals. In this pilot study, we sought to test our hypothesis by examining 34 Hispanic AD volunteers (mean age, 34.8 years) for rs1042173 genotype-based [i.e., TT versus TG/GG (Gx)] differences in subjective response to alcohol. We employed a human laboratory paradigm and analyzed the data using a linear mixed-effects model (SAS® PROC MIXED) to assess treatment, cue procedures, and genotype main effects as well as the two-way interaction effects between them. On subjective "urge to drink" and "crave for a drink," we found a significant main effect of the cue experiment (p ≤ 0.01) and an interaction effect between genotype and cue effects (p < 0.05). TT genotype was associated with higher urge to drink (p = 0.002) and crave for a drink (p = 0.005) when exposed to alcohol cue. Our results not only support the hypothesis that rs1042173 is a genetic marker for cue-induced alcohol craving among AD males but also are suggestive of a neurobiological mechanism associated with the rs1042173-TT genotype that triggers a disproportionate craving in response to alcohol consumption, which in turn may lead to more intense drinking. Future studies with larger sample sizes are needed to characterize the interactive effects of the serotonin transporter-linked polymorphic region (5'-HTTLPR)-L-allele reported in our previous study and of the rs1042173-TT genotype on cue-induced alcohol craving.
我们之前已经表明，线索诱导的酒精渴望和更高饮酒倾向受到与血清素转运体（5-HTT）表达水平改变相关的SLC6A4等位基因差异的调节。在一项独立研究中，我们对同一基因3'非翻译区（3'-UTR）中的另一种多态性SNP rs1042173进行了特征分析，该多态性也改变了5-HTT表达水平；rs1042173的T等位基因与较低的mRNA和蛋白质水平相关。在后续分析中，发现TT基因型与高加索血统的酒精依赖（AD）个体中较高的饮酒强度相关。基于这些发现，我们假设与高强度饮酒相关的低表达TT基因型将预测AD个体对酒精的更高渴望。在这项初步研究中，我们试图通过检查34名西班牙裔AD志愿者（平均年龄34.8岁）基于rs1042173基因型[即TT与TG/GG（Gx）]在对酒精的主观反应方面的差异来检验我们的假设。我们采用了人体实验室范式，并使用线性混合效应模型（SAS® PROC MIXED）分析数据，以评估治疗、线索程序和基因型的主效应以及它们之间的双向交互效应。在主观的“饮酒冲动”和“渴望饮酒”方面，我们发现线索实验有显著的主效应（p≤0.01）以及基因型和线索效应之间的交互效应（p<0.05）。当暴露于酒精线索时，TT基因型与更高的饮酒冲动（p = 0.002）和渴望饮酒（p = 0.005）相关。我们的结果不仅支持rs1042173是AD男性中线索诱导的酒精渴望的遗传标记这一假设，而且还提示了一种与rs1042173 - TT基因型相关的神经生物学机制，该机制会引发对饮酒不成比例的渴望，进而可能导致更强烈的饮酒行为。需要进行更大样本量的未来研究来表征我们之前研究中报道的血清素转运体连锁多态性区域（5'-HTTLPR）-L等位基因与rs1042173 - TT基因型对线索诱导的酒精渴望的交互作用。
