Carcinogenesis Advance Access originally published online on May 21, 2009
Carcinogenesis 2009 30(7):1186-1192; doi:10.1093/carcin/bgp122
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A specific interleukin-1B haplotype correlates with high levels of IL1B mRNA in the lung and increased risk of non-small cell lung cancer
Section of Toxicology, Department of Chemical and Biological Work Environment, National Institute of Occupational Health, N-0033 Oslo, Norway
1 Haukeland University Hospital, N-5021 Bergen, Norway
* To whom correspondence should be addressed. Tel: +47 2319 5284; Fax: +47 2319 5204; Email: shan.zienolddiny{at}stami.no
Epidemiological evidence suggests a relationship between chronic inflammation and lung cancer. Inflammation in the lung may be modulated by host genetic factors such as polymorphisms in inflammatory genes. Identification of polymorphisms in inflammatory genes may help understanding interindividual differences in susceptibility to lung cancer. We have investigated single-nucleotide polymorphisms (SNPs) and their haplotypes in the regulatory region of the IL1B gene in association to non-small cell lung cancer (NSCLC) risk. Our previous work showed that two promoter SNPs C-511T and T-31C modulated NSCLC risk. In the present study, we show that G-3893A and G-1464C located in the enhancer region of the IL1B gene may also affect this risk, with odds for developing NSCLC being 0.69 [95% confidence interval (CI), 0.52–0.92] for -3893 A-allele and 0.63 (95% CI, 0.47 – 0.83) for -1464 C-allele. The associations were particularly prominent in patients with TP53 mutations in the tumor. Inference of the haplotype structures showed that -3893 G, -1464 G, -511 C and -31 T formed a specific haplotype (GGCT) with near complete linkage disequilibrium in lung cancer patients but not in controls. Furthermore, the risk haplotype (GGCT) was present in 65% of cases compared with 36% of controls. Quantitative analysis of RNA in normal lung tissue of the patients showed that the risk haplotype was correlated with significantly higher IL1B messenger RNA (mRNA) levels compared with the non-risk haplotype (ACTC). These data suggest that a specific IL1B haplotype associated with increased IL1B gene expression increases the risk of NSCLC.
Abbreviations: BFDP, Bayesian false-discovery probability; C/EBPβ, CCAAT/enhancer-binding protein β; CI, confidence interval; FPRP, false-positive report probability; IL-1β, interleukin-1beta; LD, linkage disequilibrium; mRNA, messenger RNA; NSCLC, non-small cell lung cancer; OR, odds ratio; PCR, polymerase chain reaction; qPCR, quantitative real-time PCR; SNP, single-nucleotide polymorphism
Received April 2, 2009; revised May 8, 2009; accepted May 11, 2009.