Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch

Abstract

Polymorphisms in the dopamine D2 receptor (DRD2 C/T and DRD2 A/G) and in dopamine beta hydroxylase (DBH A/G) have been implicated in modulation of smoking and other reward-seeking behaviours. We hypothesized that these alleles would predict the outcome of nicotine patch therapy for smoking cessation. In 1991-93, we performed a randomized controlled trial of the nicotine patch on 1686 heavy smokers (> or = 15 cigarettes/day). In 1999-2000, we contacted 1532 of the 1612 subjects still available; 767 (50%) completed a questionnaire and gave a blood sample. In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation. At 1 week, the patch was more effective for smokers with DRD2 CT/TT genotype [patch/placebo odds ratio (OR) 2.8, 95% confidence interval (CI) 1.7-4.6] than with CC (OR 1.4, 0.9-2.1; P for difference in ORs 0.04). Smokers with both DRD2 CT/TT and DBH GA/AA genotypes had an OR of 3.6 (2.0-6.5) compared to 1.4 (1.0-2.1) for others (P = 0.01). At 12 weeks, the ORs for these genotypic groups were 3.6 (1.7-7.8) and 1.4 (0.9-2.3), respectively (P = 0.04). There was no association between patch effectiveness and DRD2 exon 8. Short-term effectiveness of the nicotine patch may be related to dopamine beta-hydroxylase and dopamine D2 receptor genotype. Our results support the need for further investigation into personalized therapies for smoking cessation based on individual genotype.

Interaction between variation in the D2 dopamine receptor (DRD2) and the neuronal calcium sensor-1 (FREQ) genes in predicting response to nicotine replacement therapy for tobacco dependence

“…5 Our findings indicate that smokers homozygous for the DRD2 À141 Ins benefit more from bupropion treatment and persons with Ins/Del or Del/ Del genotypes at the DRD2À141 locus respond better to behavioral counseling or NRT. 5 Results from this study and others [6][7][8] may, in the future, help practitioners maximize the therapeutic benefit of pharmacological treatments for nicotine dependence.…”

Overview of the pharmacogenomics of cigarette smoking

“…A study of heavy smokers (X15 cigs/day) randomized to transdermal nicotine patch or placebo found those with at least one Taq1 A1 allele were more likely to quit on the patch at the end of treatment (EOT) and 12 weeks follow-up, especially if the G allele of the DBH 1368G4A SNP was also present. 211 Subsequent analyses of this cohort found the TaqI A1 allele was associated with higher abstinence rates in women but not men at all time points examined (EOT, 12, 24 and 52 months, 8 years). 212 Conversely, women with the TaqI A1 genotypes appear to do worse on bupropion, reporting more side effects and relapse at 12 months follow-up.…”

“…216 It has been proposed that genotypes resulting in lower expression of D 2 receptors (TaqI A1 or -141C Del alleles) respond better to NRT, 211,216 whereas those with higher expression (TaqI A2 or À141C Ins alleles) respond better to bupropion. 214,216 Bupropion may be a better replacement for the subjective effects of smoking compared to NRT in subjects with higher levels of D 2 receptors assuming that its effect is partly mediated by its inhibition of dopamine reuptake and enhancement of dopamine levels.…”

A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation

“…The 12-month cessation data from the pharmacogenetic studies (David et al, 2007;Johnstone et al, 2004;Lerman et al, 2003) are in the form of binomial counts (Table 3), which provide information on log-odds ratios , , , and through a logistic regression model of the form of equation (3), but with genotype-specific control terms estimated as nuisance parameters specific to each study.…”