Department of Preventive Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90089, USA.
Pharmacogenomics J. 2012 Dec;12(6):521-32. doi: 10.1038/tpj.2011.30. Epub 2011 Aug 2.
We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni-corrected α-level of 5 × 10(-4) to determine system-wide significance. Four single-nucleotide polymorphisms (rs12021667, rs12027267, rs6702335, rs12039988; r2 > 0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (odds ratio (OR) = 0.5; 95% confidence interval (CI): 0.3-0.6) at end of treatment (adjusted P < 6 × 10(-5)). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P = 3.9 × 10(-5)); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR = 0.04; 95% CI: 0.01-0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.
我们对涉及尼古丁反应和大脑奖励途径的 53 个区域的基于系统的候选基因研究进行了性别分层分析，该研究纳入了两项戒烟治疗（安慰剂、安非他酮、经皮和鼻喷尼古丁替代疗法）的随机临床试验。我们针对多个相关测试调整了 P 值，并使用 Bonferroni 校正的 α 值为 5×10(-4)来确定全系统的显著性。红细胞膜蛋白带 4.1（EPB41）中的四个单核苷酸多态性（rs12021667、rs12027267、rs6702335、rs12039988；r2>0.98）在治疗结束时与吸烟戒断有显著的男性特异性边缘关联（优势比（OR）=0.5；95%置信区间（CI）：0.3-0.6）（调整后的 P<6×10(-5)）。大麻素受体 1（CNR1）中的 rs806365 在 6 个月随访时具有显著的男性特异性基因-治疗相互作用（调整后的 P=3.9×10(-5)）；在使用鼻喷的男性中，rs806365 与戒烟几率降低相关（OR=0.04；95%CI：0.01-0.2）。虽然 CNR1 在物质滥用中的作用已经得到了充分的研究，但我们首次在尼古丁文献中报道了 EPB41。
