Both CHRNA5-CHRNA3-CHRNB4 and CYP2A6 have been implicated in treatment response. For example, the effectiveness of nicotine replacement therapy (but not bupropion) has been found to be more pronounced in fast versus slow metabolizers [69]. A study has also shown that slow metabolizers tend to require fewer doses of nicotine spray but do not differ in their response to patch usage [120], although there is emerging evidence that slow metabolizers may be at higher risk for patch-related nicotine toxicity [121]. Similarly, one study showed that a high-risk haplotype comprised of variants in CHRNA5-CHRNA3-CHRNB4 predicted failed abstinence in placebo-treated subjects but not those receiving active pharmacotherapy [122], while another study reported similar findings for the placebo group but greater abstinence in those receiving nicotine replacement therapy [123]. Perhaps the most prominent of therapeutic alternatives for smoking cessation is varenicline, a partial agonist of the α4β2 nicotinic receptor subtype. Variants in CHRNA4 and CHRNB2 have been implicated in response to varenicline while variants in CHRNB4 were associated with nausea, a common side effect of medication use, which typically attenuates adherence [124].
