Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners.
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High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology seen 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.We assessed whether single nucleotide polymorphisms (SNP) in the IL-6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas.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 GENEVA Genome Wide Association Study of Lung Cancer and Smoking study. Functional relevance of the SNPs was characterized using in vitro approaches.Rs1800797 was associated with squamous cell carcinoma in miners, and with a shorter time between midpoint of the period of substantial exposure and diagnosis among the cases. Rs1800797 also was associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo(a)pyrene diolepoxide treatments.An IL-6 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 IL-6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion. .