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.
Highlights
Genome-wide association studies (GWAS) of lung cancer in European and East Asian populations have identified risk loci on chromosomes 5p15.33, 6p22.1-p21.31 and 15q25.1 [1,2,3,4,5,6,7]
Our findings provide evidence that inherited variation in the nicotinic acetylcholine receptor (nAChR) genes influences lung cancer risk in African-Americans
We identified a novel risk locus on chromosome 2q31.1 which correlates with CHRNA1 gene expression
Summary
Genome-wide association studies (GWAS) of lung cancer in European and East Asian populations have identified risk loci on chromosomes 5p15.33, 6p22.1-p21.31 and 15q25.1 [1,2,3,4,5,6,7]. Several single nucleotide polymorphisms (SNPs) on 5p15.33 and 15q25.1, which increase lung cancer risk in Europeans and Asians, have been shown to increase risk for lung cancer in African-Americans [8,9,10]. Because African-Americans have higher lung cancer incidence rates and poorer lung cancer survival than other racial and ethnic groups in the United States [11], they are disproportionately affected by this disease. Populationlevel differences in the frequency of risk alleles may account for some of the differences observed in lung cancer incidence across ancestral groups [12]. Known racial differences in tobaccorelated exposures, such as age when smoking is initiated, smoking intensity, attempts to quit and relapse behaviors, are likely to contribute to observed racial differences in lung cancer incidence [14]
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