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

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，已被证明对 动物致癌和体外致癌研究。花生四烯酸的作用被认为主要是由于 二十烷类前列腺素E_2(PGE_2)产生过剩。另一类多不饱和脂肪酸ω-3也与 同样的酶参与花生四烯酸的代谢；然而，结果是一组二十烷类化合物是抗- 煽动性的。因此，ω-3多不饱和脂肪酸的代谢可以间接抑制前列腺素E_2的产生，降低癌症风险。 在过去的几年里，已发现多种基因变异与多不饱和脂肪酸相关。目标是 建议的K99/R00裁决的目的是阐明长链多不饱和脂肪酸和 使用孟德尔随机化(MR)的结直肠肿瘤风险，一种可能避免潜在陷阱的方法 常规的观察性流行病学研究。利用精细绘图，拟议的研究将确定 关键基因座(11q12.2和6p24.2)的其他变异参与了从短到长的转换。 链多不饱和脂肪酸，以改进多不饱和脂肪酸遗传仪器。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 田纳西州大肠息肉研究(TCPS)；以及Vanderbilt的基因和表型信息 大学的去身份电子病历DNA生物库(BioVU)。具体来说，我们建议 目的：(1)对长链多不饱和脂肪酸与结直肠癌的关系进行磁共振研究 风险；(2)进行精细作图，以确定关键多不饱和脂肪酸代谢位点的额外变异，以改善 用于MR的遗传仪器；(3)评估遗传预测的长链多不饱和脂肪酸的潜在相互作用 (使用改进的基因仪器)以及阿司匹林和非类固醇抗炎药的使用(非类固醇抗炎药) 与结直肠癌风险的关系；(4)研究基因预测的长链基因与 多不饱和脂肪酸和选定的肿瘤生物标志物；以及(5)进行中介分析，以确定PGE2是否 长链多不饱和脂肪酸与结直肠腺瘤风险之间因果关系的中介。这是一项创新 这项研究将第一次使用多基因风险评分来开发工具变量，以便识别 长链多不饱和脂肪酸与结直肠癌肿瘤风险之间的潜在因果关系，并将成本- 效率很高。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之间的关系 肿瘤，这可能导致潜在的降低风险的策略。最后，建议的职业发展奖 将为候选人提供必要的额外教学和研究培训，以建立 营养学、遗传学和分子流行病学以及癌症领域的独立研究计划。

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.