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Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch

Abstract

Smokers of European ancestry (n=720) who participated in a double-blind, randomised, placebo-controlled trial of transdermal nicotine replacement therapy, were genotyped for two functional polymorphisms (variable number of tandem repeats (VNTR) and a C to T transition at position –521 (C-521T)) in the dopamine D4 receptor gene (DRD4) gene. Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism. For the DRD4 VNTR models, the main effect of treatment was significant at both 12-week (P=0.001) and 26-week (P=0.006) follow-ups, indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo. The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up (P=0.034), with possession of one or more copies of the long allele associated with reduced likelihood of cessation (17 vs 23%), but this effect was not observed at 26-week follow-up. For the DRD4 C-521T models, no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up. These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt.

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Acknowledgements

The authors thank Michael Churchman for assistance with assay development. In addition, we acknowledge Kate Hey, Sarah Roberts and Sarah Welch, who undertook data collection. This study was funded by a Cancer Research UK programme grant. Personal funding was provided to SPD by United States Public Health Service grant 1K08 DA14276-04 and the Robert Wood Johnson Foundation.

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Correspondence to S P David.

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Dr Walton has been the Chief Scientific Officer of G-Nostics Ltd. since October 2004.

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David, S., Munafò, M., Murphy, M. et al. Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch. Pharmacogenomics J 8, 122–128 (2008). https://doi.org/10.1038/sj.tpj.6500447

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