Phase I Metabolic Genes and Risk of Lung Cancer: Multiple Polymorphisms and mRNA Expression

摘要: Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested candidate genes. We analyzed 25 SNPs (some previously untested) 2101 primary cases 2120 population controls from the Environment And Genetics Lung Etiology (EAGLE) study six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, myeloperoxidase. evaluated main genotype effects genotype-smoking interactions risk overall major histology subtypes. combined effect of multiple on gene expression. Findings were prioritized based significance thresholds consistency across different analyses, accounted testing prior knowledge. Two haplotypes EPHX1 significantly associated with population. In addition, CYP1B1 CYP2A6 inversely adenocarcinoma squamous cell carcinoma risk, respectively. Moreover, association between CYP1A1 rs2606345 was modified by intensity cigarette smoking, suggesting an underling dose-response mechanism. Finally, increasing number variants at CYP1A1/A2 revealed significant protection never smokers ever smokers. Results supported differential expression non-tumor tissue samples down-regulation up-regulation SNPs. The haplotype associations emphasize be important despite null SNP-associations, warrants consideration genome-wide (GWAS). Our findings necessity post-GWAS fine mapping SNP functional assessment to further elucidate associations.