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||Multistage analysis of variants in the inflammation pathway and lung cancer risk in smokers.
||Spitz MR, Gorlov IP, Dong Q, Wu X, Chen W, Chang DW, Etzel CJ, Caporaso NE, Zhao Y, Christiani DC, Brennan P, Albanes D, Shi J, Thun M, Landi MT, Amos CI
||Cancer Epidemiol Biomarkers Prev
||BB, GEB, NEB
||BACKGROUND: Tobacco-induced lung cancer is characterized by a deregulated inflammatory microenvironment. Variants in multiple genes in inflammation pathways may contribute to risk of lung cancer. METHODS: We therefore conducted a three-stage comprehensive pathway analysis (discovery, replication, and meta-analysis) of inflammation gene variants in ever-smoking lung cancer cases and controls. A discovery set (1,096 cases and 727 controls) and an independent and nonoverlapping internal replication set (1,154 cases and 1,137 controls) were derived from an ongoing case-control study. For discovery, we used an iSelect BeadChip to interrogate a comprehensive panel of 11,737 inflammation pathway single-nucleotide polymorphisms (SNP) and selected nominally significant (P < 0.05) SNPs for internal replication. RESULTS: There were six SNPs that achieved statistical significance (P < 0.05) in the internal replication data set with concordant risk estimates for former smokers and five concordant and replicated SNPs in current smokers. Replicated hits were further tested in a subsequent meta-analysis using external data derived from two published genome-wide association studies (GWAS) and a case-control study. Two of these variants (a BCL2L14 SNP in former smokers and an SNP in IL2RB in current smokers) were further validated. In risk score analyses, there was a 26% increase in risk with each additional adverse allele when we combined the genotyped SNP and the most significant imputed SNP in IL2RB in current smokers and a 36% similar increase in risk for former smokers associated with genotyped and imputed BCL2L14 SNPs. CONCLUSIONS/IMPACT: Before they can be applied for risk prediction efforts, these SNPs should be subject to further external replication and more extensive fine mapping studies.