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Title: Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners

Background: High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development. Objectives: We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas. Methods: Genetic associations were assessed in a case–control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches. Results: We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the riskmore » allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments. Conclusions: An IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. Lastly, the associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion« less
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [2] ;  [3] ;  [3] ;  [3] ;  [1] ;  [2] ;  [1]
  1. Lovelace Respiratory Research Inst., Albuquerque, NM (United States). Lung Cancer Program
  2. St. Mary's Medical Center, Grand Junction, CO (United States). Saccomanno Research Inst.
  3. Penn State College of Medicine, Hershey, PA (United States). Dept. of Pharmacology
Publication Date:
Grant/Contract Number:
FG02-09ER64783; SC0001173
Accepted Manuscript
Journal Name:
Environmental Health Perspectives
Additional Journal Information:
Journal Volume: 124; Journal Issue: 4; Journal ID: ISSN 0091-6765
National Institute of Environmental Health Sciences
Research Org:
Lovelace Respiratory Research Inst., Albuquerque, NM (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Country of Publication:
United States
OSTI Identifier: