Genetic Modifiers of Radon-Induced Lung Cancer Risk: A Genome-Wide Interaction Study in Former Uranium Miners

Details

• Personal Author:
  Albanes D ; Aldrich MC ; Amos CI ; Andrew AS ; Bickeböller H ; Bojesen SE ; Brennan P ; Brüning T ; Brunnsstöm H ; Caporaso NE ; Chen C ; Christiani, David C. ; Doherty JA ; Fernández-Tardón G ; Field JK ; Gomolka M ; Goodman GE ; Haiman CA ; Haugen A ; Hung RJ ; Johansson M ; Johnen G ; Kiemeney B ; Lam S ; Landi MT ; Lazarus P ; Le Marchand L ; Liu G ; Manz J ; Muley TR ; Pesch B ; Rennert G ; Risch A ; Rosenberger A ; Schabath MB ; Tardon A ; Teare MD ; Wichmann H-E ; Zienolddiny S
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Genetics Lung Lung Diseases Neoplasms Occupational Exposure Occupational Health Respiratory System Respiratory Tract Diseases Safety Uranium
• Keywords:
  Author Keywords: GWAS DNA Repair Gene-environment Interaction Genes Genetic Factors Genomics Lung Cancer Occupational Exposure Radon Radon Progeny Uranium Miners

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• ISSN:
  0340-0131
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  California ; Florida ; Hawaii ; Maryland ; Massachusetts ; New Hampshire ; OSHA Region 1 ; OSHA Region 10 ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 8 ; OSHA Region 9 ; Tennessee ; Utah ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  91
• Issue:
  8
• NIOSHTIC Number:
  nn:20056532
• Citation:
  Int Arch Occup Environ Health 2018 Nov; 91(8):937-950
• Contact Point Address:
  Albert Rosenberger, Department of Genetic Epidemiology, University Medical Center, Georg August University Göttingen, Humboldtallee 32, 37073 Göttingen, Germany
• Email:
  arosenb@gwdg.de
• CAS Registry Number:
  Radon (CAS RN 10043-92-2)
• Federal Fiscal Year:
  2019
• Performing Organization:
  Harvard School of Public Health
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  International Archives of Occupational and Environmental Health
• End Date:
  20280630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:64940a8ba56f640065bf0e51d0f9232f18666a1e5121e29ebe2913585b6942b75a23f2f34a9cb0615079f415a243df317db7cd26d07e0f3d8f00248537e13458
• Download URL:
  https://stacks.cdc.gov/view/cdc/214123/cdc_214123_DS1.pdf
• File Type:
  [PDF - 999.30 KB ]