权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘