title: Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners.
abstract: 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.
  
  
  OBJECTIVE
  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. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion.
  
  
  BACKGROUND
  Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445-451; http://dx.doi.org/10.1289/ehp.1409437.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Thomas
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Snider
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Wenshu
authors.initials: W
authors.lastname: Chen
authors.forename: Derall G
authors.initials: DG
authors.lastname: Willis
authors.forename: Teara G
authors.initials: TG
authors.lastname: Carr
authors.forename: Jacek
authors.initials: J
authors.lastname: Krzeminski
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Amin
authors.initials: A
authors.lastname: Shantu
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Marty R
authors.initials: MR
authors.lastname: Jacobson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D056726:Genetic Association Studies; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D000067572:Miners; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016273:Occupational Exposure / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011886:Radon / Q000633:toxicity*; D014501:Uranium
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D014501:Uranium; D011886:Radon