Polyunsaturated fatty acids and colorectal tumor risk: a molecular and genetic epidemiology study

多不饱和脂肪酸与结直肠肿瘤风险：分子和遗传流行病学研究

• 批准号: 10304319
• 负责人: Nikhil Kishor Khankari
• 金额: $ 24.59万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304319
• 关键词: 11q12; 6p24; Address; Affect; Algorithms; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Area; Aspirin; Award; Binding; Biological Markers; Blood; Blood specimen; Caucasians; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Colorectal Polyp; Computerized Medical Record; Coxibs; DNA; Data; Diagnosis; Dinoprostone; Drug usage; Eicosanoid Production; Eicosanoids; Enzymes; Erythrocytes; Etiology; Fish Oils; Genetic; Genome; Genotype; Goals; In Vitro; Individual; Inflammatory; Intake; K-Series Research Career Programs; Knowledge; Lead; Malignant Neoplasms; Measures; Mediation; Mediator of activation protein; Mendelian randomization; Metabolism; Molecular Epidemiology; Molecular Epidemiology of Cancer; Non-Steroidal Anti-Inflammatory Agents; Observational Study; Observational epidemiology; Omega-3 Fatty Acids; Omega-6 Fatty Acids; PIK3CA gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Polyunsaturated Fatty Acids; Prevention strategy; Production; Research; Research Training; Resources; Risk; Risk Reduction; Stratification; Structural Models; Study Subject; Supplementation; Tennessee; Tissue Sample; Training; Tumor Markers; Tumor Tissue; United States; Universities; Variant; WFDC2 gene; adenoma; biobank; cancer risk; carcinogenesis; colorectal cancer prevention; colorectal cancer risk; cost efficient; cyclooxygenase 2; dietary; epidemiology study; fatty acid metabolism; genetic epidemiology; genetic variant; genome wide association study; improved; inflammatory marker; innovation; instrument; modifiable risk; nutrition; polygenic risk score; programs; tumor; urinary

PROJECT SUMMARY/ABSTRACT Arachidonic acid, a long-chain ω-6 polyunsaturated fatty acid (PUFA), has been demonstrated to affect carcinogenesis in animal and in vitro studies. The effect of arachidonic acid is believed to be largely due to overproduction of the eicosanoid, prostaglandin E2 (PGE2). The other class of PUFAs, ω-3, also bind to the same enzymes involved in arachidonic acid metabolism; however, the resulting set of eicosanoids are anti- inflammatory. Thus, ω-3 PUFA metabolism could indirectly inhibit PGE2 production and reduce cancer risk. Over the past few years, multiple genetic variants have been identified to be associated with PUFAs. The goal of the proposed K99/R00 award is to elucidate the potential causal association between long-chain PUFAs and colorectal tumor risk using Mendelian randomization (MR), an approach that may avoid potential pitfalls of conventional observational epidemiologic research. Using fine-mapping, the proposed study will identify additional variants in key loci (11q12.2 and 6p24.2) that are involved in the conversion from short- to long- chain PUFAs to improve the PUFA genetic instruments. The proposed study will utilize individual-level data from the ColoRectal Transdisciplinary Study (CORECT) consortium; blood and tissue samples from the Tennessee Colorectal Polyp Study (TCPS); and genotype and phenotype information from Vanderbilt University's de-identified electronic medical record DNA bio-repository (BioVU). Specifically, we propose the following aims: (1) to conduct a MR study for the association between long-chain PUFAs and colorectal cancer risk; (2) to conduct fine-mapping to identify additional variants in key PUFA metabolism loci to improve the genetic instruments for MR; (3) to evaluate potential interactions of genetically predicted long-chain PUFAs (using the improved genetic instrument) and use of aspirin and non-steroidal anti-inflammatory drugs (NSAID) with the risk of colorectal tumors; (4) to investigate associations between genetically predicted long-chain PUFAs and selected tumor biomarkers; and (5) to conduct a mediation analysis to determine whether PGE2 is a mediator on the causal pathway between long-chain PUFAs and colorectal adenoma risk. This innovative study will be the first to develop an instrumental variable using a polygenic risk score in order to identify potential causal association between long-chain PUFAs and colorectal cancer tumor risk, and will be cost- efficient. The proposed study will help elucidate associations between long-chain PUFAs and colorectal tumors, which could lead to potential risk reduction strategies. Lastly, the proposed career development award will equip the candidate with the additional didactic and research training necessary for building an independent research program in the areas of nutrition, genetics and molecular epidemiology, and cancer.

项目摘要/摘要 花生四烯酸是一种长链ω-6多不饱和脂肪酸（PUFA），已证明会影响 动物和体外研究中的致癌作用。蛛网膜酸的作用被认为很大程度上是由于 eicosanoid，Prostaglandin E2（PGE2）的过量生产。另一类的pufasω-3也与 参与花生四烯酸代谢的相同酶；然而，由此产生的类花生酸是抗 炎症。 ω-3 PUFA代谢可以间接抑制PGE2的产生并降低癌症风险。 在过去的几年中，已经确定多种遗传变异与PUFA有关。目标 在拟议的K99/R00奖中，旨在阐明长链PUFA和 使用孟德尔随机化（MR）的结直肠肿瘤风险，这种方法可能避免潜在的陷阱 常规观察性流行病学研究。使用精细映射，拟议的研究将确定 关键局部（11q12.2和6p24.2）中的其他变体涉及从短到长的转换 链条PUFA，以改善PUFA遗传仪器。拟议的研究将利用个人级别的数据 从大肠跨学科研究（Corect）联盟中。血液和组织样本 田纳西州大肠息肉研究（TCP）；以及范德比尔特的基因型和表型信息 大学的去识别电子病历DNA生物叛逆（BIOVU）。具体来说，我们提出了 以下目的：（1）进行长链PUFA与大肠癌之间关联的MR研究 风险; （2）进行精细映射以识别关键PUFA代谢基因座中的其他变体以改进 MR的遗传仪器； （3）评估遗传预测的长链PUFA的潜在相互作用 （使用改进的基因仪器）以及使用阿司匹林和非甾体类抗炎药（NSAID） 有结直肠肿瘤的风险； （4）研究一般预测的长链之间的关联 PUFA和选定的肿瘤生物标志物； （5）进行调解分析以确定PGE2是否为 长链PUFA和结直肠腺瘤风险之间因果途径的介体。这种创新 研究将是第一个使用多基因风险评分开发仪器变量的人，以识别 长链PUFA与结直肠癌肿瘤风险之间的潜在因果关系，将是成本 - 高效的。拟议的研究将有助于阐明长链PUFA与结直肠的关联 肿瘤可能导致潜在的降低风险策略。最后，提议的职业发展奖 将为候选人提供额外的教学和研究培训，以建造 营养，遗传学和分子流行病学和癌症领域的独立研究计划。