Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome

Abstract

Background Genetic influences on smoking cessation treatment outcome may be affected by pretreatment patient characteristics. Nicotine dependence is arguably the most salient clinical factor in smoking cessation. Methods In this secondary analysis of clinical trial data (N = 793), we examined nicotine dependence severity as a moderator of the effects of 1198 single nucleotide polymorphisms (SNPs) in 53 biologically-relevant gene regions on smoking cessation outcomes. P-values were adjusted to account for multiple correlated SNPs within a gene region; corrected system-wide significance was 5 × 10−4. Results SNP × nicotine dependence interactions reached region-wide significance for several SNPs in the Dopamine Beta Hydroxylase (DBH) locus (0.0005 < Adjusted-P < 0.05), including rs1541333, which reached system-wide significance for predicting end of treatment (EOT) abstinence (Adjusted-P = 0.0004). A haplotype including 6 DBH SNPs predicted abstinence at EOT (OR = 1.7, P = 0.001) and 6-month follow-up (OR = 1.6, P = 0.008) in those with high nicotine dependence (n = 526) but not in those with low dependence (n = 227). The DBH signal observed here may be distinct from a previously reported genome-wide significant signal for former smoking status and from the principal haplotype associated with plasma dopamine beta-hydroxylase activity. A haplotype within the Chromosome 15 Nicotinic Acetylcholine Receptor gene region predicted abstinence at EOT in those with high (OR = 2.0, P = 0.0004) but not low (P = 0.6) dependence in post hoc analyses. Conclusions Considering pre-treatment nicotine dependence level may optimize the prediction of genetic influences on cessation outcomes. If replicated, results like these may inform prognosticative genomic screening panels designed to identify smokers at high risk of relapse when coupled with severe nicotine dependence.

Biomarkers of Response to Smoking Cessation Pharmacotherapies: Progress to Date

“…Other approaches include GW pooled allelotyping [70-72], risk score analysis based on CG or GW a priori hypotheses [73-76], or pharmacokinetic hypotheses [77-81]. Studies using CG panels and stratifying by treatment, gender, nicotine metabolism, or dependence, have identified SNPs at CHRNB2 [61], multiple nAChRs and CYP2B6 [62], SLC22A2 [63], EPB41 and CNR1 [64], DRD1 [65], and at DBH [66]. …”

Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward

“…Prior research examining these SNPs reported mostly null findings (Hack et al, 2011; Koks et al, 2006; Kollins et al, 2008; Mitsuyasu et al, 2007; Nyman et al, 2007; Thomson et al, 2014). One exception is that minor allele carriers at rs12280580 were over two times more likely than major homozygotes to be abstinent 6 months after a pharmacotherapy trial, but this finding was not present in an assessment at the end of the trial, nor were there findings for rs936461 or the other 8 DRD4 SNPs examined (Leventhal et al, 2014). …”

“…Although prior research examining SNPs in DRD4 has generally failed to find significant associations with smoking-related outcomes (David et al, 2008; Hack et al, 2011; Herman et al, 2014; Leventhal et al, 2014; Munafo et al, 2006; Thomson et al, 2014), one study found that, among highly nicotine dependent smokers, minor allele carriers at DRD4 SNP rs12280580 were over two times more likely to be abstinent from cigarettes 6 months post-treatment (Leventhal et al, 2014). Examining DRD4 SNPs in relation to subjective responding to cigarettes may provide enhanced precision in evaluating the contributions of the gene region towards smoking behavior.…”

Chronic obstructive pulmonary disease risk and smoking cessation changes induced by CHRNA5-A3 and CHRNB3-A6 variation in a Chinese male population

“…We believe that genes related to nicotinedependence may affect the development of COPD. In addition, nicotine-dependence can be considered as the most significant factor for smoking cessation [4].…”