Objectives Genetic susceptibility in work-related lung cancer aetiology could have an important public health impact. Few studies have previously evaluated this issue, with inconsistent results. We aimed to investigate interactions between exposure to occupational carcinogens and genetic polymorphisms in lung cancer aetiology, adopting a systematic integrated approach.
Method EAGLE, a population-based case-control study, enrolled 2100 lung cancer cases and 2120 controls (Italy, 2002–2005). Lifetime work histories were collected for 4059 subjects and translated into exposure to six occupational carcinogens (asbestos, silica, polycyclic aromatic hydrocarbons, diesel exhausts, chromium, and nickel) using a job-exposure matrix. We selected 23 candidate genes among phase II metabolic genes reported in association with lung cancer susceptibility and/or metabolism of selected carcinogens. 298 tagging single nucleotide polymorphisms (SNPs) were genotyped on 4050 subjects. We tested for interaction within smoking-adjusted logistic regressions where SNPs were modelled individually, by gene group (using gene scores and haplotypes), and by pathways. False discovery rate (FDR) was used to account for multiple testing. Gene expression changes in lung tissues were studied for SNPs-carcinogens significant interactions.
Results As asbestos had the highest impact on lung cancer burden, we restricted interaction tests to this carcinogen. GSTM4 polymorphisms consistently showed positive interactions across different analysis levels, especially by SNP group score (FDR-adjusted p-value for interaction < 0.0001). No significant genetic “signal” by asbestos exposure was found at lung tissue level.
Conclusions GSTM4 polymorphisms may play a role in asbestos-related lung cancer aetiology. These findings are biologically plausible and have never previously been reported; they should therefore be validated in further studies.
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