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Multicenter Study
. 2012 Nov;3(11):1428-38.
doi: 10.18632/oncotarget.746.

Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans

Kyle M Walsh  1 , Christopher I Amos, Angela S Wenzlaff, Ivan P Gorlov, Jennette D Sison, Xifeng Wu, Margaret R Spitz, Helen M Hansen, Emily Y Lu, Chongjuan Wei, Huifeng Zhang, Wei Chen, Stacy M Lloyd, Marsha L Frazier, Paige M Bracci, Michael F Seldin, Margaret R Wrensch, Ann G Schwartz, John K Wiencke
Affiliations
Multicenter Study

Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans

Kyle M Walsh et al. Oncotarget. 2012 Nov.

Abstract

Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10-4). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10-5). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.

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Conflict of interest statement

The authors do not have any conflicts of interest, financial or otherwise.

Figures

Figure 1
Figure 1. Association of 16 genotyped and 305 imputed SNPs on chromosome 2q31.1 with lung cancer in African-Americans
The horizontal line indicates the study-wide Bonferroni-corrected significance threshold (1.49 × 10−4). Black diamonds denote SNPs which were directly genotyped on array. Gray circles denote imputed SNPs. Associations are adjusted for: sex, age, and % African ancestry, and combined across sites with fixed-effects meta-analysis.
Figure 2
Figure 2. Association of SNPs on chromosome 15q25.1 with lung cancer, with and without adjustment for pack-years smoked
The horizontal line indicates the study-wide Bonferroni-corrected significance threshold (1.49 × 10−4). Black squares depict association of SNPs with lung cancer, adjusted for: sex, age, and % African ancestry, and combined across sites with fixed-effects meta-analysis. Open circles depict association of SNPs with lung cancer, adjusted for: sex, age, % African ancestry, and number of pack-years smoked and combined across sites with fixed-effects meta-analysis.
See this image and copyright information in PMC

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