title: Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression.
abstract: Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and SNP functional assessment to further elucidate cancer risk associations.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Rotunno
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lubin
authors.forename: Dario
authors.initials: D
authors.lastname: Consonni
authors.forename: Angela C
authors.initials: AC
authors.lastname: Pesatori
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Goldin
authors.forename: Sholom
authors.initials: S
authors.lastname: Wacholder
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdette
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Pier Alberto
authors.initials: PA
authors.lastname: Bertazzi
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D005189:False Positive Reactions; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D050216:Metabolic Detoxication, Phase I / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012907:Smoking / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1