Pharmacogenetic Association of the Galanin Receptor (GALR1) SNP rs2717162 with Smoking Cessation

Abstract

Galanin modulates dopaminergic neurotransmission in the mesolimbic dopamine system, thereby influencing the rewarding effects of nicotine. Variants in the galanin receptor 1 (GALR1) gene have been associated with retrospective craving severity and heaviness of smoking in prior research. We investigated pharmacogenetic associations of the previously studied GALR1 polymorphism, rs2717162, in 1217 smokers of European ancestry who participated in one of three pharmacogenetic smoking cessation clinical trials and were treated with nicotine patch (n=623), nicotine nasal spray (n=189), bupropion (n=213), or placebo (n=192). The primary endpoint was abstinence (7-day point prevalence, biochemically confirmed) at the end of treatment. Cravings to smoke were assessed on the target quit day (TQD). The longitudinal regression model revealed a significant genotype by treatment interaction (P=0.03). There was a reduced odds of quitting success with the presence of at least one minor (C) allele in the bupropion-treated group (OR=0.43; 95% CI=0.22-0.77; P=0.005) but equivalent quit rates by genotype in the nicotine-replacement therapy groups. This genotype by treatment interaction was reproduced in a Cox regression model of time to relapse (P=0.04). In the bupropion trial, smokers carrying the C allele also reported more severe TQD cravings. Further research to identify functional variants in GALR1 and to replicate pharmacogenetic associations is warranted.

Gender Considerations in Addiction: Implications for Treatment

“…While some research found genotype effects on treatment response in women but not men (e.g., 53, 54), others found no evidence of sex differences (e.g., 55, 56). Sex hormones and their impact on dopamine (DA) reward pathways must also be considered and add complexity.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…In a clinical context, craving for tobacco (nicotine) is a major challenge for individuals with nicotine dependence, and craving is one of the most important factors contributing to smoking relapse. Two studies on smokers of European ancestry reported an association of an intronic SNP in the GAL 1 gene with smoking cessation (Lori et al, 2011;Gold et al, 2012) (Table 6). …”

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

“…Different genes that belong neither to the cascade of reward nor to the nicotine metabolism are also associated with SC: the C-allele of GALR1 (rs2717162) decreases SC [55] and the T-allele of HINT1 (rs3852209) increases SC at 6-month follow-up [56]. …”

“…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).…”