Dopamine D4 receptor gene variation moderates the efficacy of bupropion for smoking cessation

Abstract

Smokers (≥10 cig/day; N =331) of European ancestry taking part in a double-blind placebo-controlled randomized trial of 12 weeks of treatment with bupropion plus counseling for smoking cessation were genotyped for a VNTR polymorphism in Exon-III of the Dopamine D4 receptor (DRD4) gene. Generalized estimating equations predicting point-prevalence abstinence at end of treatment and 2, 6, and 12-months post-end of treatment indicated that bupropion (vs. placebo) predicted increased odds of abstinence. The main effect of Genotype was not significant. A Genotype × Treatment interaction (p=.005) showed that bupropion predicted increased odds of abstinence in long-allele carriers (OR=1.31, p<.0001), whereas bupropion was not associated with abstinence among short-allele homozygotes (OR=1.06, p=.23). The Genotype × Treatment interaction remained when controlling for demographic and clinical covariates (p=.01) and in analyses predicting continuous abstinence (ps≤.054). Bupropion may be more efficacious for smokers who carry the long-allele, which is relevant to personalized pharmacogenetic treatment approaches.

Environmental and Genomic Factors as well as Interventions Influencing Smoking Cessation: A Systematic Review of Reviews and a Proposed Working Model

“…One study reports that the G-allele improved SC [35]; another confirms this in women but reports an increased SC in men with AA-genotype [36]. Dopamine influences SC through some variants, but some results could not be replicated in different studies [37,38,39,40,41,42,43,44,45,46,47]. The A1-allele of DRD2 Taq1A [38] and the long-allele of DRD4 VNTR [48] appear to reduce SC.…”

“…Interactions with nicotine replacement therapy are observed for OPRM1 A118G [36], DRD4 VNTR [48], COMT Val 108/158 Met [43], CHRNB2 rs2072661 [52], and GALR1 rs2717162 [55]. Bupropion interacts with SLC6A4 5-HTTLPR [34], DRD2 TaqIA [42,47], DRD2- 141C [41], DRD4 VNTR [45], CYP2B6 *6 [120], and GALR1 rs2717162 [55]. Finally, rimonabant interacts with DRD2 Taq1A [44] (table 2).…”

Effects of Nicotine Deprivation and Replacement on BOLD-fMRI Response to Smoking Cues as a Function of DRD4 VNTR Genotype

“…In the alcohol literature, DRD4 L status has been associated with greater cue reactivity in two studies (Hutchison et al, 2003;McGeary et al, 2006), but not in two other studies van den Wildenberg et al, 2007). In terms of smoking cessation, although several studies have linked the DRD4 S genotype to success (e.g., Bergen et al, 2012;David et al, 2008;Laucht et al, 2005Laucht et al, , 2008Leventhal et al, 2012), others have found no association (Huang et al, 2005;Luciano et al, 2004). Clearly, there is considerable ambiguity with regard to the role of DRD4 VNTR in nicotine dependence, and there is a need for larger, more systematic studies to clarify this relationship.…”

“…In particular, the 48-bp variable number tandem repeat (VNTR) polymorphism (Asghari et al, 1995;Van Tol et al, 1991 in the third exon of the DRD4 gene has been associated with tobacco dependence Shields et al, 1998), cue reactivity (Hutchison, LaChance, Niaura, Bryan, & Smolen, 2002;McClernon, Hutchison, Rose, & Kozink, 2007), and smoking cessation (Bergen et al, 2012;David et al, 2008;Leventhal et al, 2012). Although classification schemes for this polymorphism vary (Wang et al, 2004), alleles have generally been grouped into "long" (L; seven or more repeats) or "short" (S; six or fewer) most consistently in the literature (Munafò et al, 2003).…”

“…Compatible evidence has also come from a study of smoking-related attentional processing, in which DRD4 VNTR status moderated performance on a modified Stroop task that included smoking-related words , but this was only present among ex-smokers, not among current smokers. The DRD4 L allele has also been associated with smoking status, initiation, and lower point-prevalence smoking abstinence (David et al, 2008;Huang et al, 2005;Laucht, Becker, El-Faddagh, Hohm, & Schmidt, 2005;Laucht et al, 2008;Leventhal et al, 2012;Luciano et al, 2004;MacKillop, Menges, McGeary, & Lisman, 2007;Ton et al, 2007;van den Wildenberg, Janssen, Hutchison, van Breukelen, & Wiers, 2007;see McGeary, 2009 for review).…”