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

描述(由申请人提供)：个体间药理反应的差异对疾病治疗的发病率和死亡率有很大影响。遗传变异是这种变异的一个主要来源。然而，尽管 在过去的20年里，为了确定基因和其他导致药物反应变化的原因，进行了大量的研究工作，但仍有许多未知之处。我们推测，这是基因-环境-药物(GED)和多基因-药物(PGD)相互作用的一部分结果。虽然在这一领域进行研究的挑战是相当大的，但我们相信，通过发展合理的机制假设和仔细设计基础研究和翻译研究，可以在理解GED和PGD相互作用方面取得重大进展。在这项计划项目拨款申请中，我们提出了三个高度互动的研究项目和两个支持核心，它们将共同开发和应用新的、可推广的方法，在通过使用抗凝和抗血小板药物治疗预防心血管疾病患者的血栓栓子事件的背景下，了解和预测GED和PGD的相互作用。环境暴露和抗凝/抗血小板药物与维生素K依赖的凝血和血小板激活级联反应的相互作用为研究GED和PGD的影响提供了一个难得的机会。这一努力的核心将是我们与西北部和阿拉斯加的美国印第安人和阿拉斯加原住民(AI/AN)人群的持续合作，他们具有独特的且往往定义明确的饮食和其他环境暴露，初步数据表明，这些暴露可以改变凝血途径和血小板功能；丰富独特的、具有重要功能的基因类型；与美国总体人口相比，总体上降低了基因组异质性。此外，在道德上迫切需要与人工智能/AN人群进行健康研究，因为他们经常被排除在这类调查之外，因此得不到这类研究所能提供的潜在好处。因此，我们的总体计划目标是：1)促进我们对遗传和环境因素如何影响抗凝和抗血小板药理反应的理解，以及2)更广泛地改善与AI/AN人群进行基因组研究的国家环境。

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.