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Cancer Epidemiol Biomarkers Prev. 2012 Jul;21(7):1213-21. doi: 10.1158/1055-9965.EPI-12-0352-T. Epub 2012 May 9.

Multistage analysis of variants in the inflammation pathway and lung cancer risk in smokers.

Author information

  • 1Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. spitz@bcm.edu

Abstract

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.

©2012 AACR

PMID:
22573796
[PubMed - indexed for MEDLINE]
PMCID:
PMC3487592
Free PMC Article

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