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Lookup NU author(s): Professor Dawn Teare
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Springer Verlag, 2018.
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© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. Methods: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. Results: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11–0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10−6), 5q23.2 (p = 2.5 × 10−6), 1q21.3 (p = 3.2 × 10−6), 10p13 (p = 1.3 × 10−5) and 12p12.1 (p = 7.1 × 10−5). Genes belonging to the Gene Ontology term “DNA dealkylation involved in DNA repair” (GO:0006307; p = 0.0139) or the gene family HGNC:476 “microRNAs” (p = 0.0159) were enriched with LD-blockwise significance. Conclusion: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.
Author(s): Rosenberger A, Hung RJ, Christiani DC, Caporaso NE, Liu G, Bojesen SE, Le Marchand L, Haiman CA, Albanes D, Aldrich MC, Tardon A, Fernandez-Tardon G, Rennert G, Field JK, Kiemeney B, Lazarus P, Haugen A, Zienolddiny S, Lam S, Schabath MB, Andrew AS, Brunnsstom H, Goodman GE, Doherty JA, Chen C, Teare MD, Wichmann H-E, Manz J, Risch A, Muley TR, Johansson M, Brennan P, Landi MT, Amos CI, Pesch B, Johnen G, Bruning T, Bickeboller H, Gomolka M
Publication type: Article
Publication status: Published
Journal: International Archives of Occupational and Environmental Health
Print publication date: 01/11/2018
Online publication date: 03/07/2018
Acceptance date: 28/06/2018
Date deposited: 12/11/2019
ISSN (print): 0340-0131
ISSN (electronic): 1432-1246
Publisher: Springer Verlag
PubMed id: 29971594
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