These finding suggest a hypothesis that can be tested in treatment-seeking smokers. Smokers with reduced α5 subunit function and associated increased nicotine dependence might be expected to have more difficulty quitting. The observation in this analysis that smokers with reduced α5 subunit function treated with NRT have increased overall abstinence rates, and the increased direct effect of rs1051730 on abstinence in mediation analysis, reflect a mechanism that is distinct from the effects of rs1051730 on nicotine dependence, and of nicotine dependence upon abstinence. Prescribed NRT may improve cognitive performance that assists abstinent smokers to maintain normal brain functioning after quitting smoking, and this effect may be stronger for individuals carrying the risk allele of rs1051730. Retrospective analyses of RCT arms randomizing individuals to PLA or NRT, and/or a prospective genotype and NRT-stratified trial, with the appropriate genetic, behavioral and cognitive function data, could test this hypothesis.
