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

• 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
• 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

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存在许多相似之处，并且由于免疫监测消除了早期的肿瘤细胞，因此人们对癌症中炎症和先天免疫的作用一直具有长期的兴趣。这些关系被认为与大肠癌（CRC）特别相关，因为它与炎症性肠病史建立了良好的牢固联系，并使用了非甾体类抗炎药，并且在不断受到康复性细菌刺激的非常丰富的免疫系统的肠道中存在。拟议的研究将使用现有数据和来自结肠癌家族登记册（CCFR）和多民族队列（MEC）的标本来检验以下假设，即在炎症和先天免疫途径中遗传了关键基因中遗传变异的假设会导致促炎的易感性易感性和弱细胞毒性防御，从而增加了CRC的危险。我们建议在AIM 1中使用参与结肠CFR的白色不一致的Sibpair进行病例对照研究（2,488例CRC病例，4,280个对照），以测试CRC与这些途径中基因中约700个TAGSNP的关联。根据生物学相关性和功能证据对所选的38个基因进行了优先排序。对于每个基因座，将使用链接不平衡（R2> 0.9，MAF> 0.05）从主要由HAPMAP构建的密集的SNP映射中选择TAGSNP。在AIM 2中，我们将在AIM 1中测试大约10％的最密切相关的SNP，以及在这些基因座和AIMS中的其他TAGSNP，在MEC中嵌套的第二个病例对照研究（2,768例CRC病例和2,768例对照）中，以验证发现和调查跨种族/种族效应的异质性。基于家庭的设计将完全保护AIM 1免受人口分层的影响。 AIM 2将利用MEC参与者的遗传和生活方式异质性以及其暴露数据的前瞻性性质，以控制I型错误，评估跨种族/种族种群的效应异质性，并研究GXG和GXE相互作用。遗传变体在炎症或与先天免疫相关的基因与CRC中的关联将证实该癌症持续性的，临床上炎症的病因作用。它还可以提供一种识别易感子组的方法，这些小组可能特别受益于NSAIDS化学预防和筛查。公共卫生相关性：拟议的研究将检验炎症和先天免疫相关基因与结直肠癌的遗传变异的关联，以确认该癌症的持续性，临床炎症的病因作用。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类炎症药物的强化筛查和/或初级预防。