In summary, six SNPs in DRD1
have significant gene × nicotine metabolism ratio interactions with smoking abstinence at EOT. The minor alleles for these SNPs were associated with significantly increased abstinence rates within slow metabolizers. We find that gene × nicotine metabolism interactions are more strongly associated with smoking abstinence than unstratified gene effects. Prior studies have also shown associations between DRD1
polymorphisms and nicotine dependence [14
]. The SNPs in DRD1
that interacted with NMR in our study are neither found in prior nicotine dependence studies nor in LD with SNPs reported in previous studies, but they may be in LD with an undiscovered functional variant for nicotine dependence and D1 dopamine receptor expression.
In the absence of information on the functional consequences of the relevant DRD1
variants, the mechanism of the interaction with the rate of nicotine metabolism is unknown. Nicotine exposure has been shown to upregulate D1 dopamine receptor expression and activity in key brain regions important for nicotine reward [15
]. Such upregulation may contribute to the level of nicotine dependence, and the extent of upregulation may be influenced by the rate of nicotine metabolism.
The association for rs1051730 in the chr15q25.1 nAChR region replicates previous findings between this SNP and nicotine dependence. An interaction was reported between rs1051730 and CYP2A6
, where cigarette consumption and FTND both increased for those in increasing risk categories (homozygous for the rs1051730 minor allele and/or normal nicotine metabolizers as determined by CYP2A6
]. This is consistent with our finding, where normal nicotine metabolizers as assessed by NMR carrying the rs1051730 minor allele are more likely to relapse.
Strengths and limitations have been described previously [4
]. Strengths include bias reduction through baseline biomarker measurements and the prospective assessment of abstinence. Also, our P
-value adjustment for multiple correlated test is less conservative than a Bonferroni adjustment. However, while gene effects have been shown to differ across treatments [4
], we lack a sufficient sample to detect small gene × NMR × treatment interaction effects.
In summary, we observe significant gene × NMR interactions in which six DRD1 SNPs are associated with increased odds of smoking abstinence with slow nicotine metabolizers. We also replicate previous findings for an interaction between rs1051730 in the chr15q25.1 nAChR region and the rate of nicotine metabolism. Independent validation of our results is necessary before more conclusions can be made from these findings.