Landvik Nina E, Hart Kent, Skaug Vidar, Stangeland Lodve B, Haugen Aage, Zienolddiny Shanbeh
Section of Toxicology, Department of Chemical and Biological Work Environment, National Institute of Occupational Health, Oslo, Norway.
Carcinogenesis. 2009 Jul;30(7):1186-92. doi: 10.1093/carcin/bgp122. Epub 2009 May 21.
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.
流行病学证据表明慢性炎症与肺癌之间存在关联。肺部炎症可能受宿主遗传因素如炎症基因多态性的调节。鉴定炎症基因中的多态性可能有助于理解个体对肺癌易感性的差异。我们研究了白细胞介素1β（IL1B）基因调控区的单核苷酸多态性（SNP）及其单倍型与非小细胞肺癌（NSCLC）风险的关系。我们之前的研究表明，两个启动子SNP，即C-511T和T-31C，可调节NSCLC风险。在本研究中，我们发现位于IL1B基因增强子区域的G-3893A和G-1464C也可能影响这种风险，-3893 A等位基因发生NSCLC的比值比为0.69 [95%置信区间（CI），0.52 - 0.92]，-1464 C等位基因的比值比为0.63（95% CI，0.47 - 0.83）。这些关联在肿瘤中存在TP53突变的患者中尤为显著。单倍型结构推断显示，-3893 G、-1464 G、-511 C和-31 T在肺癌患者中形成了一种具有近乎完全连锁不平衡的特定单倍型（GGCT），而在对照组中则没有。此外，65%的病例存在风险单倍型（GGCT），而对照组中这一比例为36%。对患者正常肺组织中的RNA进行定量分析表明，与非风险单倍型（ACTC）相比，风险单倍型与显著更高的IL1B信使核糖核酸（mRNA）水平相关。这些数据表明，与IL1B基因表达增加相关的一种特定IL1B单倍型会增加NSCLC的风险。
