Inflammation and Innate Immunity Genes and Colorectal Cancer Risk

描述：由于慢性炎症和恶性过程之间有许多相似之处，并且由于免疫监视可以消除早期肿瘤细胞，因此炎症和先天免疫在癌症中的作用长期以来一直受到关注。这些关系被认为与结直肠癌（CRC）特别相关，因为它与炎症性肠病史和非甾体抗炎药的使用有很强的相关性，并且肠道中存在一个非常丰富的免疫系统，该系统不断受到共生细菌的刺激。拟议的研究将使用结肠癌家族登记处（CCFR）和多种族队列（MEC）的现有数据和标本来验证炎症和先天免疫途径中关键基因的遗传变异导致促炎易感和弱细胞毒性防御，从而增加结直肠癌风险的假设。在Aim 1中，我们建议使用参与结肠CFR的White不一致兄弟姐妹（2488例CRC病例，4280例对照）进行病例对照研究，以测试CRC与这些途径中基因中约700个标签snp的相关性。选择的38个基因根据生物学相关性和功能证据进行优先排序。对于每个位点，将使用连锁不平衡（R2>0.9， MAF>0.05）从主要由HapMap构建的密集SNP图中选择标签SNP。在Aim 2中，我们将在第二项病例对照研究（2768例CRC病例和2768例对照）中测试Aim 1中大约10%的最强烈相关snp，以及这些位点和AIMs上的额外标签snp，以验证研究结果并调查跨民族/种族群体效应的异质性。以家庭为基础的设计将充分保护目标1免受人口分层。目的2将利用MEC参与者的遗传和生活方式异质性以及他们暴露数据的前瞻性来控制I型误差，评估不同民族/种族人群的效应异质性，并调查GxG和GxE的相互作用。炎症或先天免疫相关基因的遗传变异与结直肠癌的关联将证实这种癌症中持续的亚临床炎症的病因学作用。它也可能提供一种方法来确定易感的亚群，这些亚群可能特别受益于非甾体抗炎药的化学预防和筛选。公共卫生相关性：拟议的研究将测试炎症和先天免疫相关基因的遗传变异与结直肠癌的关系，以确认持续的亚临床炎症对结直肠癌的致病作用。它还可以提供一种方法来确定易感亚群，这些亚群可能特别受益于强化筛查和/或非甾体类炎症药物的一级预防。

DESCRIPTION: Because of the many similarities between chronic inflammation and the malignant process, and because of the elimination of early neoplastic cells by immune surveillance, there has been a long standing interest in the role of inflammation and innate immunity in cancer. Theses relationships are thought to be particularly relevant to colorectal cancer (CRC) because of its well-established strong associations with history of inflammatory bowel disease and use of non-steroidal anti-inflammatory drug, and the presence in the gut of a remarkably abundant immune system that is constantly stimulated by commensal bacteria. The proposed study will use existing data and specimens from the Colon Cancer Family Registry (CCFR) and the Multiethnic Cohort (MEC) to test the hypothesis that inherited variants in key genes in the inflammation and innate immunity pathways result in a pro-inflammatory predisposition and weak cytotoxic defense that confer an increased risk of CRC. We propose in Aim 1 to conduct a case-control study using the White discordant sibpairs participating in the Colon CFR (2,488 CRC cases, 4,280 controls) to test the association of CRC with ~700 tagSNPs in genes in these pathways. The 38 genes selected were prioritized based on biological relevance and functional evidence. For each locus, tagSNPs will be selected using linkage disequilibrium (R2>0.9, MAF>0.05) from a dense SNP map constructed primarily from HapMap. In Aim 2, we will test approximately 10% of the most strongly associated SNPs in Aim 1, as well as additional tagSNPs at these loci and AIMs, in a second case-control study (2,768 CRC cases and 2,768 controls) nested in the MEC, in order to validate the findings and investigate heterogeneity of effects across ethnic/racial groups. The family-based design will fully protect Aim 1 against population stratification. Aim 2 will take advantage of the genetic and lifestyle heterogeneity of MEC participants and of the prospective nature of their exposure data to control Type I error, assess effect heterogeneity across ethnic/racial populations, and investigate GxG and GxE interactions. The association of inherited variants in inflammation or innate immunity-related genes with CRC would corroborate the etiologic role of persistent, sub-clinical inflammation in this cancer. It may also provide a means to identify susceptible sub-groups which may particularly benefit from NSAIDs chemoprevention and screening. PUBLIC HEALTH RELEVANCE: The proposed study will test the association of inherited variants in inflammation and innate immunity-related genes with colorectal cancer in order to confirm the causative role of persistent, sub-clinical inflammation for this cancer. It may also provide a means to identify susceptible sub-groups which may particularly benefit from intensive screening and/or primary prevention with non-steroidal inflammatory drugs.