Jensen Kevin P, DeVito Elise E, Herman Aryeh I, Valentine Gerald W, Gelernter Joel, Sofuoglu Mehmet
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
VA Connecticut Healthcare System, West Haven, CT, USA.
Neuropsychopharmacology. 2015 Nov;40(12):2813-21. doi: 10.1038/npp.2015.131. Epub 2015 May 7.
Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a protocol that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968A; frequency=28% (EA) and 6% (AA)) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the association of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.
全基因组关联研究表明，CHRNA5-CHRNA3-CHRNB4基因簇与重度吸烟风险以及多种吸烟相关疾病有关。重度吸烟风险等位基因可能会降低尼古丁的厌恶效应，但这一假设尚未在人体中得到验证。我们评估了CHRNA5基因中一个候选因果变异rs16969968对欧美（EA）和非裔美国（AA）吸烟者（n = 192；50%为AA；73%为男性）尼古丁急性反应的影响。在夜间戒除尼古丁后，参与者完成了一项方案，包括静脉注射一剂生理盐水和两剂递增的静脉注射尼古丁。评估的结果包括尼古丁效应的厌恶、愉悦和刺激评分、对尼古丁的心血管反应性、戒断严重程度以及尼古丁给药前后的认知表现。重度吸烟风险等位基因（rs16969968A；频率=28%（EA）和6%（AA））与厌恶效应评分较低相关（P<5×10^(-8)），具有明显的特异性。在作为单独组分析的EA和AA受试者中，这种效应很明显，并且在最高尼古丁剂量时最为显著。Rs16969968A还与尼古丁给药后认知控制测量指标（Stroop任务）的更大改善相关。这些发现支持对尼古丁的不同厌恶反应是CHRNA5-CHRNA3-CHRNB4与重度吸烟关联的一种可能机制。
