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

Journal Article · · Environmental Health Perspectives
DOI:https://doi.org/10.1289/ehp.1409437· OSTI ID:1393408
 [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
+ Show Author Affiliations

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 risk 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

Research Organization:
Lovelace Respiratory Research Inst., Albuquerque, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Grant/Contract Number:
FG02-09ER64783; SC0001173
OSTI ID:
1393408
Journal Information:
Environmental Health Perspectives, Vol. 124, Issue 4; ISSN 0091-6765
Publisher:
National Institute of Environmental Health SciencesCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 18 works
Citation information provided by
Web of Science

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Cited By (8)

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners journal July 2018
Potential screening assays for individual radiation sensitivity and susceptibility and their current validation state journal July 2019
Local and Systemic Inflammation May Mediate Diesel Engine Exhaust–Induced Lung Function Impairment in a Chinese Occupational Cohort journal November 2017
Interleukin-6 gene polymorphisms and susceptibility to liver diseases journal December 2019
Circular RNA profiles in mouse lung tissue induced by radon journal April 2017
Novel Genetic Associations Between Lung Cancer and Indoor Radon Exposure journal December 2018
The Effect of lnterleukin-6 Gene Polymorphism on Pediatric Pneumonia journal July 2020
Histopathologic Analysis of Lung Cancer Incidence Associated with Radon Exposure among Ontario Uranium Miners journal October 2018

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