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:
- 金额:$ 24.76万
- 依托单位:
- 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:
- 关键词:11q126p24AddressAffectAlgorithmsAnimalsAnti-Inflammatory AgentsArachidonic AcidsAreaAspirinAwardBindingBiological MarkersBloodBlood specimenCaucasiansColorectalColorectal AdenomaColorectal CancerColorectal NeoplasmsColorectal PolypComputerized Medical RecordCoxibsDNADataDiagnosisDinoprostoneDrug usageEicosanoid ProductionEicosanoidsEnzymesErythrocytesEtiologyFish OilsGeneticGenomeGenotypeGoalsIn VitroIndividualInflammatoryIntakeK-Series Research Career ProgramsKnowledgeLeadMalignant NeoplasmsMeasuresMediationMediator of activation proteinMendelian randomizationMetabolismMolecular EpidemiologyMolecular Epidemiology of CancerNon-Steroidal Anti-Inflammatory AgentsObservational StudyObservational epidemiologyOmega-3 Fatty AcidsOmega-6 Fatty AcidsPIK3CA genePathway interactionsPatientsPharmaceutical PreparationsPhenotypePlasmaPolyunsaturated Fatty AcidsPrevention strategyProductionResearchResearch TrainingResourcesRiskRisk ReductionStratificationStructural ModelsStudy SubjectSupplementationTennesseeTissue SampleTrainingTumor MarkersTumor TissueUnited StatesUniversitiesVariantWFDC2 geneadenomabiobankcancer riskcarcinogenesiscolorectal cancer preventioncolorectal cancer riskcost efficientcyclooxygenase 2dietaryepidemiology studyfatty acid metabolismgenetic epidemiologygenetic variantgenome wide association studyimprovedinflammatory markerinnovationinstrumentmodifiable risknutritionpolygenic risk scoreprogramstumorurinary
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nikhil Kishor Khankari其他文献
Nikhil Kishor Khankari的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nikhil Kishor Khankari', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 24.76万 - 项目类别:
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:
10560524 - 财政年份:2021
- 资助金额:
$ 24.76万 - 项目类别:
相似海外基金
Mechanistic studies of the genetic contribution of desmoplakin to pulmonary fibrosis in alveolar type 2 cells
桥粒斑蛋白对肺泡2型细胞肺纤维化的遗传贡献机制研究
- 批准号:
10736228 - 财政年份:2023
- 资助金额:
$ 24.76万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 24.76万 - 项目类别:
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:
10560524 - 财政年份:2021
- 资助金额:
$ 24.76万 - 项目类别:
A genetic approach to identify the common mechanisms of vascular disease
识别血管疾病常见机制的遗传学方法
- 批准号:
10477676 - 财政年份:2019
- 资助金额:
$ 24.76万 - 项目类别:
Single cell analysis of gene expression in human vascular cells
人类血管细胞基因表达的单细胞分析
- 批准号:
9810454 - 财政年份:2019
- 资助金额:
$ 24.76万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
9919442 - 财政年份:2019
- 资助金额:
$ 24.76万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
10004934 - 财政年份:2019
- 资助金额:
$ 24.76万 - 项目类别:
Functional Characterization of Coronary Artery Disease Loci
冠状动脉疾病基因座的功能特征
- 批准号:
9764460 - 财政年份:2018
- 资助金额:
$ 24.76万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
9298804 - 财政年份:2016
- 资助金额:
$ 24.76万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
9263835 - 财政年份:2016
- 资助金额:
$ 24.76万 - 项目类别: