An independent sample of smokers with the rs2236196 polymorphism reported increased sensitivity to the acute effects of smoking after 8 h of abstinence and subjects treated with nasal spray maintained treatment gains at 6 months follow-up (Hutchison et al. 2007). In addition, CHRNA4 SNP rs2236196, as well as rs3787138 and rs6062899, were associated with abstinence in smokers treated with varenicline, consistent with varenicline’s molecular target (King et al. 2011). rs2236196 is located in the 3′ end of the untranslated region of the CHRNA4 gene and alters an mRNA biding site for the iron-responsive element (IRE). Nucleotide substitutions lead to a significant loss of binding affinity for IRE (Erlitzki et al. 2002; Hentze et al. 2004; Jaffrey et al. 1993) and IREs have been found to regulate translation of genes involved in CNS function (Rogers et al. 2002). The association of rs2236196 with changes in sensitivity to the acute effects of nicotine and with response to nicotine therapy may be a result of changes at the protein level, which may lead to a change in CNS sensitivity to cholinergic stimulation (Hutchison et al. 2007).
