Gender Stratified Gene and Gene–Treatment Interactions in Smoking Cessation

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 SNPs (rs12021667, rs12027267, rs6702335, rs12039988; r(2)>0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (OR=0.5; 95% 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.