NLRP1和NLRP3炎症小体及下游基因遗传多态与食管癌易感性及其功能学研究

Esophageal cancer (EC) is of top fourth leading cause of cancer deaths and the fifth most common diagnosed cancer in China in 2009. NLRP1 and NLRP3 inflammasome may lead to the production of the active forms of interleukin 1β (IL-1β) and IL-18, which might contribute to cancer etiology. Single nucleotide polymorphisms (SNPs) may be important for EC susceptibility. Our recent studies have found some of inflammasome downstream IL-1β SNPs were significantly associated with EC susceptibility. The aim of our study is to thoroughly investigate inflammasome associated SNPs and EC risk. We use HapMap and high throughput genotype testing technology (SNPseq) and advanced molecular biology methods, conduct a hospital based two-stage case-control study, to investigate: (1) The association between inflammasome related SNPs and EC susceptibility; (2) Gene-gene and gene-environment (smoking, drinking, etc.) interactions; (3) The biological function of SNPs related with EC risk. We can obtain benefit from the results for early diagnosis and treatment of EC.

食管癌(Esophageal cancer, EC)在中国人群中的肿瘤死亡原因中排第4位，在常见肿瘤的诊断中排第5位。NLRP1和NLRP3炎症小体能促进白介素1β, 白介素18等炎症因子成熟，在EC发病过程中起重要作用。我们前期研究发现炎症小体下游基因白介素1β多态性和EC易感性存在显著关联。然而，上述关联不能全面的描述炎症小体相关基因多态性在EC易感性中的影响，研究只是对炎症小体个别相关基因进行初步的研究和分析，本研究采用大样本量，以医院为基础的两阶段病例对照研究，选择NLRP1和NLRP3炎症小体及其下游基因标签位点，深入探讨①NLRP1和NLRP3炎症小体及其下游基因的遗传多态单独或联合与中国人群EC易感性的关联；②NLRP1和NLRP3炎症小体及其下游基因的基因-基因，基因-环境交互作用；③功能性多态性位点的生物学功能。对EC的早期诊断、早期治疗等，研究结果具有重要意义。

食管癌的发生是环境和遗传因素共同作用的结果，但确切的遗传变异尚不明确。本研究借助人类单倍型数据库（Hapmap）和高通量基因型检测技术以及其它先进的分子生物学方法，深入探讨了1. NLRP1, NLRP3的遗传多态（SNPs）与食管癌易感性的关联；2.白细胞介素家族相关基因SNPs与食管癌易感性的关联。3.其它易感基因（如CTLA-4, CCND1等）SNPs与食管癌易感性的关联。4.功能学研究方面，选择白介素IL-1β rs16944，IL-12B rs3212227 (3′UTR A>C), IL-17A rs3819025三个位点进行双荧光素酶报告基因检测。5.食管癌二代测序的研究。我们发现NLRP1, NLRP3 标签多态性位点可能与食管癌易感性无明显相关，IL1β rs16944 G>A可能是食管癌的保护性因素。CTLA-4, CCND1与食管癌的发病风险无关，研究结果对食管癌的早期诊断、早期治疗等，具有重要意义。