Program on Genetic and Dietary Predictors of Drug Response in Rural and AI/AN Populations

农村和 AI/AN 人群药物反应的遗传和饮食预测因子计划

基本信息

批准号：
9767815
负责人：
WYLIE G. BURKE
金额：
$ 152万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767815
关键词：
Admixture Affect Alaska Alaska Native American Indians Anticoagulants Anticoagulation Antiplatelet Drugs Applications Grants Area Biochemical Cardiovascular Agents Cardiovascular Diseases Clinical Clinical Trials Coagulation Process Collaborations Communities Data Development Diet Dietary Factors Disease Drug Interactions Environment Environmental Exposure Environmental Risk Factor Event General Population Genes Genetic Genetic Variation Genomics Genotype Goals Health Healthcare Heterogeneity Individual Institution Investigation Knowledge Lead Left Marketing Modeling Morals Morbidity - disease rate Native-Born Pacific Northwest Pathway interactions Pharmaceutical Preparations Pharmacogenomics Pharmacology Pharmacotherapy Platelet Activation Polyunsaturated Fatty Acids Population Population Study Prevalence Procedures Program Research Project Grants Research Research Project Grants Risk Sample Size Scientist Site Source Technology Testing Therapeutic Translational Research Tribes Universities Variant Venous Thrombosis Vitamin K base community based participatory research community consultation cost design drug response prediction genetic variant improved individual response mortality novel personalized medicine pharmacogenetic testing platelet function prevent programs public health relevance response rural Americans sound success translational study

项目摘要

DESCRIPTION (provided by applicant): Interindividual differences in pharmacological response contribute significantly to the morbidity and mortality often associated with therapeutic treatments of disease. Genetic variation represents a major source of this variability. Yet despite considerable research effort over the past 20 years to identify genetic and other causes of variable drug response, much remains unknown. We posit that this is the result in part of unrecognized gene-environment-drug (GED) and polygenic-drug (PGD) interactions. While the challenges in conducting research in this area are considerable, we believe that significant inroads to understanding GED and PGD interactions can be made by developing sound mechanistic hypotheses and careful design of basic and translational studies. In this Program Project grant application, we propose three, highly interactive research Projects, and two supporting Cores, that together will develop and apply novel, generalizable approaches to understanding and predicting GED and PGD interactions in the context of preventing thromboembolic events in individuals with cardiovascular disease through the use of anticoagulation and antiplatelet drug therapies. The interaction of environmental exposures and anticoagulation/antiplatelet drugs with the vitamin K-dependent coagulation and platelet activation cascades offers an exceptional opportunity to study GED and PGD effects. Central to this effort will be our continued collaboration with American Indian and Alaska Native (AI/AN) populations of the Northwest and Alaska who have unique and often well-defined dietary and other environmental exposures that preliminary data suggests modify the coagulation pathway and platelet function; enrichment of unique, functionally important genotypes; and reduced genomic heterogeneity overall, compared to the general US population. Moreover, there is a strong moral imperative to conduct health research with AI/AN people, as they are often left out of such investigations and, thus, do not receive the potential benefits that such research can provide. Thus, our overall Program goals are to: 1) to advance our understanding of how genetic and environmental factors affect anti-coagulation and anti-platelet pharmacological responses, and 2) to more broadly improve the national environment for genomic research with AI/AN populations.

描述（由申请人提供）：药理学反应的个体差异显着导致与疾病治疗治疗相关的发病率和死亡率。遗传变异代表了这种变异性的主要来源。尽管如此在过去的20年中，大量的研究工作以确定遗传和其他导致药物反应的原因，这仍然是未知的。我们认为，这是未识别的基因环境 - 药物（GED）和多基因毒品（PGD）相互作用的结果。尽管在该领域进行研究的挑战是相当大的，但我们认为，可以通过开发声音机械假设以及对基本和翻译研究的仔细设计来理解GED和PGD相互作用的重要侵害。在此计划项目授予应用程序中，我们提出了三个高度互动的研究项目，以及两个支持核心，它们将共同开发和采用可概括的，可概括的方法来理解和预测GED和PGD相互作用，以防止通过使用抗凝凝集和抗血小板药物治疗的患有心血管疾病的人群中血栓栓塞事件。环境暴露和抗凝/抗血小板药物与维生素K依赖性凝血和血小板激活级联反应的相互作用为研究GED和PGD效应提供了极大的机会。这项工作的核心将是我们与西北和阿拉斯加的美洲印第安人和阿拉斯加人（AI/AN）人口的持续合作，他们具有独特的饮食和其他定义明确的饮食和其他环境暴露，这些初步数据表明修改了凝血途径和血小板功能；富集独特的，功能上重要的基因型；与美国普通人群相比，总体上降低了基因组异质性。此外，与AI/AN人进行健康研究是有强烈的道德要求，因为他们通常被排除在此类调查之外，因此没有获得此类研究可以提供的潜在利益。因此，我们的整体计划目标是：1）提高我们对遗传和环境因素如何影响抗凝凝和抗血域药理学反应的理解，以及2）更广泛地改善AI/A AN人群的基因组研究的国家环境。