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

描述（由申请方提供）：药理学反应的个体间差异显著导致通常与疾病治疗相关的发病率和死亡率。遗传变异是这种变异性的主要来源。然而尽管 尽管过去20年来进行了大量研究，以确定可变药物反应的遗传和其他原因，但仍有许多未知之处。我们认为这是未被识别的基因-环境-药物（GED）和多基因药物（PGD）相互作用的结果。虽然在这一领域进行研究的挑战是相当大的，我们认为，重大的进展，了解GED和PGD的相互作用，可以通过发展健全的机制假设和精心设计的基础和转化研究。在这个项目资助申请中，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，可推广的方法来理解和预测GED和PGD的相互作用，通过使用抗凝和抗血小板药物治疗来预防心血管疾病患者的血栓栓塞事件。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活化级联反应的相互作用为研究GED和PGD效应提供了一个绝佳的机会。这项工作的核心将是我们继续与美国西北部和阿拉斯加的美洲印第安人和阿拉斯加原住民（AI/AN）群体合作，他们具有独特且通常定义明确的饮食和其他环境暴露，初步数据表明，与美国普通人群相比，这些暴露改变了凝血途径和血小板功能;丰富了独特的功能重要的基因型;并降低了整体基因组异质性。此外，与AI/AN人进行健康研究具有强烈的道德责任，因为他们经常被排除在此类调查之外，因此无法获得此类研究所能提供的潜在利益。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学反应的理解，2）更广泛地改善AI/AN人群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.