Nicotinic acetylcholine receptor beta2 subunit gene implicated in a systems-based candidate gene study of smoking cessation

Abstract

Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated, there is substantial variability among individuals in treatment response. We performed a systems-based candidate gene study of 1295 single nucleotide polymorphisms (SNPs) in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a bupropion placebo-controlled randomized clinical trial. Putative functional variants were supplemented with tagSNPs within each gene. We used global tests of main effects and treatment interactions, adjusting the P-values for multiple correlated tests. An SNP (rs2072661) in the 3' UTR region of the beta2 nicotinic acetylcholine receptor subunit (CHRNB2) has an impact on abstinence rates at the end of treatment (adjusted P = 0.01) and after a 6-month follow-up period (adjusted P = 0.0002). This latter P-value is also significant with adjustment for the number of genes tested. Independent of treatment at 6-month follow-up, individuals carrying the minor allele have substantially decreased the odds of quitting (OR = 0.31; 95% CI 0.18-0.55). Effect of estimates indicate that the treatment is more effective for individuals with the wild-type (OR = 2.14, 95% CI 1.20-3.81) compared with individuals carrying the minor allele (OR = 0.83, 95% CI 0.32-2.19), although this difference is only suggestive (P = 0.10). Furthermore, this SNP demonstrated a role in the time to relapse (P = 0.0002) and an impact on withdrawal symptoms at target quit date (TQD) (P = 0.0009). Overall, while our results indicate strong evidence for CHRNB2 in ability to quit smoking, these results require replication in an independent sample.

Figure 1.

Block structure for CHRNB2 from HapMap Genome Build 36. The linkage disequilibrium (LD) plot was obtained using Haploview (25) and HapMap Build 36. The scale at the top of the figure depicts the HapMap region for CHRNB2 (Chromosome 1: 152,806,881 to 152,818,975), and roughly 10 kb upstream and downstream of this region. Single nucleotide polymorphisms (SNPs) genotyped by HapMap are identified in blue (minor alleles) and red (major alleles). Gene regions with the direction of their respective reading frame, exons, and introns, are also given. The 13 SNPs in boxes are the tagSNPs selected in this gene region. rs2072658 and rs2072661 have no HapMap or LD information. The r² LD color scheme is depicted. Two blocks are delineated using the default block definitions from Haploview.

Figure 2.

Abstinence rates by CHRNB2 rs2072661 and by bupropion treatment. Abstinence rates comparing individuals with at least one variant allele for CHRNB2 rs2072661 (filled bars) to those with both common alleles (unfilled bars) were stratified by treatment (buproprion or placebo) and estimated at each time point (end of treatment and 6-month follow-up).

Figure 3.

Time to relapse to 6-month follow-up for CHRNB2 rs2072661. Time to relapse to 6-month follow-up in individuals with at least one variant allele for CHRNB2 rs2072661 (thin lines) was compared with those having both alleles common (thick lines), stratifying by treatment group: buproprion (dotted lines) and placebo (solid lines).