This study provides evidence for association of a common 3’UTR SNP in the β2 subunit nAChR gene with responsiveness to nicotine patch effects on abstinence in a one week simulated quit attempt. Specifically, those with the CHRNB2 GG genotype quit on more days with the nicotine versus placebo patch, compared to those with the AA or AG genotypes. In addition, nicotine patch increased the probability of quitting on the target quit day, quitting anytime during the patch week, and avoiding relapse during the week after initiating abstinence among those with the GG genotype but not AA/AG genotypes, although the interaction of nicotine x genotype was significant only for quitting on the target quit day. Therefore, our results suggest a rather specific benefit of nicotine patch in those with the GG genotype, that of enhancing their ability to initiate abstinence on the scheduled target quit day.
association with ability to quit due to nicotine versus placebo patch is consistent with the results of a prior pharmacogenetic study (11
). Among participants in a randomized clinical trial of bupropion versus placebo, the odds of being abstinent at 6-month follow-up were significantly greater among smokers with the GG genotype than those with the AG or AA genotype, and there was a trend for greater responsiveness to bupropion in this group as well. Thus, genetic variation in CHRNB2
may be related to greater therapeutic response to cessation medications in general, or to medications acting on a mechanism which is shared by nicotine patch and bupropion. Conti et al. (11
) also found an overall greater odds of abstinence at the end of 12 weeks of treatment, regardless of medication condition, for the GG genotype versus AG/AA, a main effect of CHRNB2
genotype we also observed for quitting on the target quit day, but not for quitting on any day or avoiding relapse once quit.
Although nicotine patch reduced craving, patch effects on craving and withdrawal did not reveal genotype differences in those responses to nicotine versus placebo patch that might help explain the greater quitting of those with the GG versus AG or AA genotypes. Yet, those analyses were exploratory in that they were limited to only those days when subjects were abstinent, so that responses to nicotine via patch would not be confounded with effects due to nicotine via smoking. Restricting these analyses to abstinent subjects may also introduce self-selection bias, as those unable to abstain may have experienced the most severe withdrawal. Possible genetic influences on craving and withdrawal responses to NRT should be examined in larger samples during enforced periods of abstinence to reduce the self-selection bias (i.e. ability to quit each patch week) that may have obscured our results on craving and withdrawal. Moreover, smoking history and demographic characteristics did not differ between CHRNB2
genotypes (), consistent with prior studies (6
) and suggesting that the greater ability of those with the GG genotype to quit with nicotine patch is not due to a difference in level of dependence or smoking behavior, but rather to unique influences on the ability to quit.
These results are limited in several ways, and the associations of CHRNB2
with quitting success on nicotine patch require replication. First, our sample of 156 was small for genetic analyses, although the within-subjects design greatly enhanced power by allowing subjects to act as their own controls (see 17
). Moreover, power in the ANOVA was further augmented by our continuous dependent measure of abstinence of the number of days quit, compared with the dichotomous dependent measure of abstinent versus relapsed typical in clinical trials. Second, in addition to the possible bias in the analysis of withdrawal and craving, noted previously, our sample may have been biased due to self-selection of smokers interested in participating in a short-term simulated clinical trial, rather than an actual clinical trial. Third, and similarly, the genotype differences in quitting due to nicotine patch may have been specific to the procedures or short duration of this simulated trial, and our findings need to be confirmed in an actual clinical trial of nicotine versus placebo patch involving long-term follow-up, as in the bupropion trial reported by Conti et al. (11
Further studies are needed to determine whether the SNP in the present study has functional properties or is in linkage disequilibrium with unknown functional variants in CHRNB2
. Building on the results from Conti et al. (11
) with bupropion and the current study with NRT patch, such research should also examine associations of CHRNB2
with clinical response to other formulations of NRT and particularly to the other FDA-approved cessation medication, varenicline (ChantixR
), which is a partial agonist of α4β2 nicotine receptors (5