Nicotinic Acetylcholine Receptor Region on Chromosome 15q25 and Lung Cancer Risk Among African Americans: A Case–Control Study

Abstract

Genome-wide association studies of white persons with lung cancer have identified a region of extensive linkage disequilibrium on chromosome 15q25.1 that appears to be associated with both risk for lung cancer and smoking dependence. Because studying African American persons, who exhibit lower levels of linkage disequilibrium in this region, may identify additional loci that are associated with lung cancer, we genotyped 34 single-nucleotide polymorphisms (SNPs) in this region (including LOC123688, PSMA4, CHRNA5, CHRNA3, and CHRNB4 genes) in 467 African American patients with lung cancer and 388 frequency-matched African American control subjects. Associations of SNPs in LOC123688 (rs10519203; odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.25 to 2.05, P = .00016), CHRNA5 (rs2036527; OR = 1.67, 95% CI = 1.26 to 2.21, P = .00031), and CHRNA3 (rs1051730; OR = 1.81, 95% CI = 1.26 to 2.59, P = .00137) genes with lung cancer risk reached Bonferroni-corrected levels of statistical significance (all statistical tests were two-sided). Joint logistic regression analysis showed that rs684513 (OR = 0.47, 95% CI = 0.31 to 0.71, P = .0003) in CHRNA5 and rs8034191 (OR = 1.76, 95% CI = 1.23 to 2.52, P = .002) in LOC123688 were also associated with risk. The functional A variant of rs1696698 in CHRNA5 had the strongest association with lung cancer (OR = 1.98, 95% CI = 1.25 to 3.11, P = .003). These SNPs were primarily associated with increased risk for lung adenocarcinoma histology and were only weakly associated with smoking phenotypes. Thus, among African American persons, multiple loci in the region of chromosome 15q25.1 appear to be strongly associated with lung cancer risk.

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

“…There is strong a priori evidence for the role of genes making up the chr15q25.1 nicotinic acetylcholine receptor (nAChR) region ( CHRNA5-CHRNA3-CHRNB4 ) in nicotine dependence (Amos et al, 2010; Falcone et al, 2011; Wassenaar et al, 2011), therefore, we investigated their effects in a post hoc analysis. At EOT, 7 SNPs (rs684513, rs667282, rs637137, rs3743078, rs938682, rs4887069, rs6495309) in the cluster of genes comprising the chr15q25.1 nAChR region had associations within the FTND-High group that achieved region-wide, but not system-wide, significance (ORs = 1.7–2.2, 0.003 ≤ Adjusted P s < 0.03).…”

Association of the 15q25 and 5p15 Lung Cancer Susceptibility Regions with Gene Expression in Lung Tumor Tissue

“…This approach would be particularly useful in African-Americans who exhibit lower levels of LD, thus permitting better localization of association signals. Fine mapping studies that examine the association of SNPs in this region with risk in African-Americans have already been undertaken (30,31). In addition, resequencing of this region would further reveal its genetic architecture and may lead to detection of de novo variants at or near IREB2 that are causally related to expression of this gene.…”

The Alpha 9-Nicotinic Acetylcholine Receptor Serves as a Molecular Target for Breast Cancer Therapy

“…28 An association between common variants in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25 and lung cancer risk has recently been reported. 29 In turn, these findings led our group to hypothesize that human airway epithelial cells express all of the components required to synthesize and secrete members of the ACh family and nAChR subtypes.…”