Abstract
Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29–1.62, P = 3.69×10−10) and 1.35 (95% CI: 1.18–1.55, P = 9.99×10−6) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10−5 and P = 5.65×10−3). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating - lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94–1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk.
Highlights
An association between common variants in the CHRNA5CHRNA3-CHRNB4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25 and lung cancer risk has recently been reported [1,2,3]; notably with the single nucleotide polymorphism (SNP) rs1051730 and highly correlated SNPs
The association between the 15q25 locus tagged by rs16969968/rs1051730 and other correlated SNPs has been robustly replicated for smoking related traits including, cigarettes per day (CPD) and heavy smoking, in both candidate gene studies [5] and recent large meta-analyses of genome-wide association (GWA) data [6,7,8]
It has been argued that the association with CPD is not sufficient to explain the association between 15q25 variation and lung cancer risk [9], suggesting a direct role for 15q25 in lung cancer development
Summary
An association between common variants in the CHRNA5CHRNA3-CHRNB4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25 and lung cancer risk has recently been reported [1,2,3]; notably with the single nucleotide polymorphism (SNP) rs1051730 and highly correlated SNPs (including rs12914385) This association was first identified directly through genome-wide association (GWA) studies of lung cancer conducted by Amos et al [1] and Hung et al [2]. The observation of higher lung cancer risks in lower smoking-exposed strata and in individuals with a family history of the disease has been interpreted to implicate 15q25 variants in both smoking behaviour and directly in lung cancer [10] Support for this assertion comes from the finding that lung cancer risks associated with 15q25 variants have been reported to be essentially unchanged after adjusting for CPD [9]. To provide increased power to demonstrate a relationship between 15q25 genotype and lung cancer risk in never-smokers, we conducted a meta-analysis, pooling our study findings with previously published data
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