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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

基本信息

批准号：
10338200
负责人：
Nikhil Kishor Khankari
金额：
$ 24.76万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10338200
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

项目摘要

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.

项目概要/摘要花生四烯酸是一种长链 ω-6 多不饱和脂肪酸 (PUFA)，已被证明可以影响动物和体外研究中的致癌作用。花生四烯酸的作用被认为很大程度上是由于类二十烷酸、前列腺素 E2 (PGE2) 的过量产生。另一类 PUFA，ω-3，也与参与花生四烯酸代谢的酶相同；然而，由此产生的类二十烷酸具有抗- 炎症。因此，ω-3 PUFA代谢可以间接抑制PGE2的产生并降低癌症风险。在过去的几年里，多种遗传变异已被确定与多不饱和脂肪酸有关。目标拟议的 K99/R00 奖项的目的是阐明长链 PUFA 与使用孟德尔随机化 (MR) 来评估结直肠肿瘤风险，这种方法可以避免潜在的陷阱常规观察流行病学研究。使用精细绘图，拟议的研究将确定关键位点（11q12.2 和 6p24.2）中的其他变异参与从短到长的转换链 PUFA 以改进 PUFA 遗传仪器。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；血液和组织样本来自田纳西州结直肠息肉研究（TCPS）；以及来自范德比尔特大学的基因型和表型信息大学的去识别化电子病历 DNA 生物存储库 (BioVU)。具体来说，我们建议目标如下：（1）针对长链PUFA与结直肠癌之间的关联进行MR研究风险; (2) 进行精细定位，以确定关键 PUFA 代谢位点的其他变异，以改善 MR 遗传仪器； (3) 评估基因预测的长链 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抗炎药（NSAID）有结直肠肿瘤的风险； (4) 研究基因预测的长链之间的关联 PUFA 和选定的肿瘤生物标志物； (5) 进行中介分析以确定 PGE2 是否长链 PUFA 与结直肠腺瘤风险之间因果关系的中介因素。这种创新的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，以便识别长链 PUFA 与结直肠癌肿瘤风险之间存在潜在因果关系，并且成本较高高效的。拟议的研究将有助于阐明长链 PUFA 与结直肠癌之间的关联肿瘤，这可能会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建立一个必要的额外教学和研究培训营养、遗传学和分子流行病学以及癌症领域的独立研究计划。