title: Multistage analysis of variants in the inflammation pathway and lung cancer risk in smokers.
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.
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. spitz@bcm.edu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Gorlov
authors.forename: Qiong
authors.initials: Q
authors.lastname: Dong
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: David W
authors.initials: DW
authors.lastname: Chang
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Etzel
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Michael
authors.initials: M
authors.lastname: Thun
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000473:pathology*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics*; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D015996:Survival Rate
chemical_list: C428448:BCL2L14 protein, human; C508020:IL2RB protein, human; D053646:Interleukin-2 Receptor beta Subunit; D019253:Proto-Oncogene Proteins c-bcl-2