Pharmacodynamic Candidate Genes

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5.2.1 Nicotinic Pathway Genes

A functional polymorphism on the CHRNA4 gene (rs2236196) has been associated with response to NRT (Hutchison et al, 2007).

Compared to participants with a TC genotype at this SNP locus, participants in other genotype groups were more likely to be abstinent on the nicotine nasal spray, but not the nicotine patch (Hutchison et al, 2007).

5.2.2 Dopaminergic Pathway Genes

The ANKK1 T allele was associated with greater response to the nicotine patch among women (Yudkin et al, 2004), as well as individuals who had the A/* genotype for dopamine beta-hydroxylase (DBH) (Johnstone et al, 2004b). However, these findings were not confirmed in a larger cohort study (Munafo et al, 2009a). Two functional polymorphisms on DRD2 (-141 Ins/DelC & C957T) were tested for association with response to NRT. At the end of treatment participants homozygous for the DelC allele had a more favorable response to NRT (Lerman et al, 2006a); and, there was evidence for an interaction between this polymorphism and a dopamine receptor interacting gene (FREQ) for predicting abstinence after NRT (Dahl et al, 2006). For the C957T polymorphism, participants possessing the C/* allele were more likely to be abstinent after NRT regardless of treatment form (patch vs. spray) (Lerman et al, 2006a). The Met/Met (low activity) COMT genotype group was associated with greater likelihood of abstinence with nicotine patch (Johnstone et al, 2007; Munafo et al, 2008) and a threefold increase in quitting success in women regardless of NRT form (patch vs. spray) (Colilla et al, 2005). The DRD4 7-repeat allele has been associated with lower abstinence rates on the nicotine patch (David et al, 2008), while no effect on abstinence was observed for the -521 promoter polymorphism located on DRD4 (Munafo et al, 2006b). Smokers carrying the 9-repeat allele for the SLC6A3 VNTR were more likely to be abstinent than individuals that possessed the 10/10 genotype (O'Gara et al, 2007; Stapleton et al, 2007).

5.2.3 Serotonergic Pathway Genes

The 5-HTTLPR VNTR repeat polymorphism has not demonstrated any pharmacogenetic associations with NRT in two published studies evidence for interaction with OPRM1 genotype (David et al, 2007b; Munafo et al, 2006a). and quitting success on NRT (Ray et al, 2007a).

5.2.4 Endogenous Opioid Pathway Genes

The OPRM1 gene has been associated with NRT treatment outcome in two studies. The first study observed that the G allele at the A118G locus was associated with better quit rates on the nicotine patch, quicker recoveries from a cigarette lapse, significant decline in negative mood symptoms during the first two weeks of abstinence, and lower weight gain compared to A/A genotype individuals (Lerman et al, 2004). The second study observed an opposite finding in that participants with the A/A genotype had higher quit rates on nicotine patch, compared with placebo, with no difference in quit rates on either nicotine patch or placebo for the */G allele participants (Munafo et al, 2007). However, when these results were examined by gender, female participants with the */G allele were more likely to quit on nicotine patch compared to placebo patch (Munafo et al, 2007). Further, the discrepancy between the two studies could be due to the fact that the latter study (Munafo et al, 2007) was able to only collect genetic information retrospectively on 50% of the original population that participated in the clinical trial whereas Lerman and colleagues collected genotype data prospectively on all participants in their study; partial ascertainment in a genetic study can contribute bias. Additional reasons for the opposing findings could be the differing ancestries of the two populations tested; however, the similar minor allele frequencies across the populations argue against this. The two studies also differ in terms of study design as all the study population studied by Lerman and colleagues received NRT (patch vs. spray) while the population studied by Munafo and colleagues compared active NRT (i.e., nicotine patch) to placebo treatment. Lastly, the differing findings between one or both studies could be reflective of a type 1 error. Mu-opioid receptor interacting proteins ARRB2 and protein kinase-c inhibiting proteins (HINT1) did not show any

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