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.

项目总结/摘要 花生四烯酸，一种长链ω-6多不饱和脂肪酸（PUFA），已被证明影响 在动物和体外研究中的致癌作用。花生四烯酸的作用被认为主要是由于 类花生酸，前列腺素E2（PGE 2）的过度生产。另一类PUFA ω-3也结合于 同样的酶参与花生四烯酸代谢;然而，所得的类花生酸是抗- 煽动性因此，ω-3 PUFA代谢可间接抑制PGE 2的产生，降低癌症风险。 在过去的几年中，已经确定了多种遗传变异与PUFA相关。目标 拟议的K99/R 00奖项的目的是阐明长链PUFA与 结直肠肿瘤风险使用孟德尔随机化（MR），这种方法可以避免潜在的陷阱， 传统的观察性流行病学研究。使用精细映射，拟议的研究将确定 关键基因座（11q12.2和6p24.2）中的其他变异参与了从短到长的转换， 链PUFA以改进PUFA遗传工具。拟议的研究将利用个人层面的数据 来自结肠直肠跨学科研究（CORECT）联盟的血液和组织样本; 田纳西结直肠息肉研究（TCPS）;基因型和表型信息来自范德比尔特 大学的去识别电子病历DNA生物库（BioVU）。具体来说，我们建议 目的：（1）进行长链多不饱和脂肪酸与结直肠癌相关性的MR研究 风险;（2）进行精细定位，以确定关键PUFA代谢基因座的其他变体，以改善 MR的遗传仪器;（3）评估遗传预测的长链PUFA的潜在相互作用 （使用改进的遗传仪器）和使用阿司匹林和非甾体抗炎药（NSAID） 与结直肠肿瘤的风险;（4）调查遗传预测的长链 PUFAs和选定的肿瘤生物标志物;和（5）进行介导分析以确定PGE 2是否是 长链多不饱和脂肪酸和结直肠腺瘤风险之间因果途径的介导者。这一创新 这项研究将是第一个使用多基因风险评分开发工具变量的研究， 长链多不饱和脂肪酸和结直肠癌肿瘤风险之间的潜在因果关系，并将是成本- 高效.这项拟议的研究将有助于阐明长链多不饱和脂肪酸与结直肠癌之间的关系。 肿瘤，这可能导致潜在的风险降低策略。最后，拟议的职业发展奖 将为候选人提供额外的教学和研究培训，以建立一个 在营养学、遗传学和分子流行病学以及癌症领域的独立研究项目。