Inflammation and Innate Immunity Genes and Colorectal Cancer Risk

炎症和先天免疫基因与结直肠癌风险

基本信息

批准号：
8110526
负责人：
LOIC LE MARCHAND
金额：
$ 56.57万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2012-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8110526
关键词：
African African American American Anti-Inflammatory Agents Anti-inflammatory Apoptotic Asians Australia Bacteria Biological Canada Cancer Family Candidate Disease Gene Case-Control Studies Chemoprevention Chronic Clinical Cohort Studies Colon Colorectal Cancer DNA Data Disease Drug usage Environment European Family Family-Based Registry GDF15 gene Genes Genetic Genetic Epistasis Genetic Polymorphism Genetic Variation Genotype Hawaii Hawaiian population Health Heterogeneity Homeostasis IKBKB IL12A gene IL1A gene IL6 gene IL8 gene Immune system Immunologic Surveillance Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inherited Interleukin-10 Interleukin-15 Japanese American Latino Lesion Life Style Linkage Disequilibrium Los Angeles Lymphoid Malignant - descriptor Malignant Neoplasms Maps Methods Morbidity - disease rate Mucous Membrane Mutation NF-kappa B Natural Immunity Nature Non-Steroidal Anti-Inflammatory Agents PPARG gene PTGS1 gene PTGS2 gene Participant Pathway interactions Patients Pattern recognition receptor Pharmaceutical Preparations Play Population Predisposition Primary Prevention Process Prostaglandin E Receptor Prostaglandins Race Reactive Oxygen Species Recording of previous events Risk Role Sampling Screening procedure Single Nucleotide Polymorphism Map Specimen Staging Stratification Subgroup Syndrome System TGFB1 gene TGFBR1 gene TLR1 gene TNF gene Testing Tissues Variant adenoma anakinra antiangiogenesis therapy base cancer genetics cancer risk chemokine cohort colon cancer family registry commensal microbes cytokine cytotoxic design high risk human WFDC2 protein interest mortality neoplastic cell population based prospective racial and ethnic response tumor

项目摘要

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.

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，因此长期以来人们对炎症和先天免疫在癌症中的作用产生了兴趣。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病史和非甾体类抗炎药的使用密切相关，并且肠道中存在非常丰富的免疫细胞系统不断受到共生细菌的刺激。拟议的研究将使用来自结肠癌家族登记处 (CCFR) 和多种族队列 (MEC) 的现有数据和样本来检验以下假设：炎症和先天免疫途径中关键基因的遗传变异导致促炎症倾向和细胞毒性防御能力较弱，导致结直肠癌风险增加。我们在目标 1 中建议使用参与结肠 CFR 的白人不一致同胞对（2,488 例 CRC 病例，4,280 例对照）进行病例对照研究，以测试 CRC 与这些通路中基因中约 700 个 tagSNP 的关联。根据生物学相关性和功能证据对所选的 38 个基因进行优先排序。对于每个基因座，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 图谱中选择 tagSNP。在目标 2 中，我们将在 MEC 中的第二个病例对照研究（2,768 个 CRC 病例和 2,768 个对照）中测试目标 1 中约 10% 最强相关的 SNP，以及这些位点和 AIM 上的其他 tagSNP ，以验证研究结果并调查跨种族/种族群体影响的异质性。以家庭为基础的设计将充分保护目标1免受人口分层的影响。目标 2 将利用 MEC 参与者的遗传和生活方式异质性及其暴露数据的前瞻性性质来控制 I 型错误，评估跨种族/种族人群的效应异质性，并研究 GxG 和 GxE 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持续性、亚临床炎症在这种癌症中的病因作用。它还可以提供一种识别易感亚组的方法，这些亚组可能特别受益于非甾体抗炎药化学预防和筛查。公共健康相关性：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联，以确认持续性亚临床炎症对这种癌症的致病作用。它还可以提供一种识别易感亚组的方法，这些亚组可能特别受益于使用非类固醇炎症药物的强化筛查和/或一级预防。