Role of Functional Genetic Variation in the Dopamine D2 Receptor (DRD2) in Response to Bupropion and Nicotine Replacement Therapy for Tobacco Dependence: Results of Two Randomized Clinical Trials

Abstract

Although bupropion and nicotine replacement therapy (NRT) are efficacious tobacco dependence treatments, there is substantial interindividual variability in therapeutic response and most smokers relapse. Pharmacogenetics research may improve treatment outcomes by identifying genetic variants predictive of therapeutic response. We investigated the roles of two functional genetic variants in the dopamine D2 receptor (DRD2) gene in response to pharmacotherapy for tobacco dependence among participants in two randomized clinical trials with a 6-month follow-up period: a double-blind placebo-controlled trial of bupropion (n=414) and an open label trial of transdermal nicotine vs nicotine nasal spray (n=368). At the end of the treatment phase, a statistically significant (p=0.01) interaction between the DRD2 - 141C Ins/Del genotype and treatment indicated a more favorable response to bupropion among smokers homozygous for the Ins C allele compared to those carrying a Del C allele. By contrast, smokers carrying the Del C allele had statistically significantly (p=0.006) higher quit rates on NRT compared to those homozygous for the Ins C allele, independent of NRT type. The C957T variant was also associated (p=0.03) with abstinence following NRT. These results suggest that bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 - 141 Ins C allele, while NRT may be more beneficial for those who carry the Del C allele. Study findings require confirmation in additional larger samples before they are applied in practice.

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

“…Consistent with the role of NCS-1 in modulating dopamine D2 receptor signaling, 12 we found evidence for a statistically significant interaction between a common variant in the FREQ gene (rs1054879) and a functional variant in the DRD2 promoter, DRD2 À141 Ins/Del. This finding builds upon our previous report indicating that smokers with at least one copy of the DRD2 À141 Del allele have higher abstinence rates when treated with NRT, 5 and suggests that this enhanced response to treatment is present only for the subset of smokers who also are homozygous for the A allele of FREQ rs1054879; 62% of these smokers were abstinent at EOT compared with abstinence rates of 29-38% among other groups of smokers. This effect is independent of type of NRT and is present (although diminished) at 6-month follow-up, consistent with a pharmacogenetic effect.…”

“…As shown in Table 1, there was a significant effect of time point, with a lower odds of abstinence at 6 months compared to EOT. As previously reported, 5 the main effect of DRD2 À141 Ins/Del was also significant. There was no evidence for interacting effects of either FREQ SNP with treatment type.…”

“…There was no evidence for interacting effects of either FREQ SNP with treatment type. Finally, as previously reported, 5 analyses of 41 random SNPs provided no evidence of population stratification in this sample.…”

“…Previously, we examined the role of two putative functional variations in the DRD2 gene, À141 Ins/Del and C957T, in the therapeutic outcomes of bupropion and NRT treatment for nicotine 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.…”

“…15,16 It should be noted that we also examined whether the FREQ SNPs modified the effect of the DRD2 À141 Ins/Del on response to bupropion in a placebo-controlled bupropion trial for smoking cessation. 5 In that trial, we found no evidence for an association of the FREQ SNPs with smoking cessation or response to bupropion therapy, or modulation of the DRD2À141 effect. There are several possible explanations for the lack of a FREQ SNP by DRD2À141 interaction in the bupropion trial.…”