Differences in sensitivity to cigarettes during early experimentation may help to explain the disparate trajectories of individuals who go on to become regular smokers and those who do not. While our ability to reach conclusions about genetic associations with all variables of interest was limited by sample size, the gene-association analysis in the present study indicates that minor alleles at rs16969968 may have contributed to smoking by enhancing the reinforcing effects of nicotine in nicotine-naive individuals who went on to become regular smokers. Moreover, smoking-experience analyses indicate that these effects involved both positive and negative experiences. Taking into account other recent studies, the findings suggest that early smoking experiences may mediate nicotine dependence, involving not only alpha-5 subunits but possibly also beta-2 subunits [19] as well as alpha-6 and beta-3 subunits [20]. Entrainment of nicotine dependence via enhanced sensitivity to nicotine also provides a plausible mechanism for explaining findings from three closely related investigations showing that risk of smoking and lung cancer is associated with a group of genes in chromosome 15 coding for alpha-3, alpha-5 and beta-4 nicotine receptor
