African American Cardiovascular pharmacogenetic CONsorTium (ACCOuNT): discovery and translation

非裔美国人心血管药物遗传学联盟 (ACCOuNT)：发现和转化

• 批准号: 9494074
• 负责人: DAVID O MELTZER
• 金额: $ 61.55万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9494074
• 关键词: Address; Adverse effects; Adverse event; Affect; African; African American; Alternative Splicing; American; Anticoagulants; Area; Biological; Cardiovascular Agents; Cardiovascular system; Cessation of life; Communities; Data Set; Databases; Disease; Disease susceptibility; Dose; Drug Targeting; European; Gene Expression; Gene Expression Regulation; Genetic; Genetic Markers; Genetic Variation; Genomics; Genotype; Health Care Costs; Individual; Individual Differences; Literature; Measures; Methodology; Mission; Oral; Outcome; Outcome Study; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Physicians; Pilot Projects; Population; Prediction of Response to Therapy; Quantitative Trait Loci; RNA Splicing; Race; Reaction; Recommendation; Regulation; Research; Research Infrastructure; Research Personnel; Resources; Role; Scientific Inquiry; Single Nucleotide Polymorphism; Source; Testing; Translations; Variant; Warfarin; Whole Blood; Work; clinical phenotype; clinically relevant; clopidogrel; cohort; drug development; feeding; genetic association; genetic predictors; genetic variant; genome wide association study; genomic data; improved; insight; interest; novel; patient oriented; personalized approach; precision medicine; predictive marker; response; therapy outcome; transcriptome; transcriptomics

Pharmacogenomics is aimed at identifying genetic variation (SNPs) that influence inter-individual differences in drug response and adverse events and has widespread clinical relevance. Its application promises to enable targeted drug administration, improve therapeutic outcome, and inform drug development. Pharmacogenomic insights have improved our understanding of the underlying pathways and mechanisms behind adverse drug reactions, which account for approximately 100,000 deaths per year in the US and markedly increase healthcare costs. The vast majority of pharmacogenomic association studies, which are the drivers of discovery in the field of precision medicine, have been conducted on exclusively European populations, thereby precluding the discovery of African American specific genetic biomarkers that affect drug phenotypes. Without scientific inquiry on the presence and association of these SNPs to drug response, our ability to deliver precision medicine to 1 in 7 Americans is severely hampered. To close this growing heath disparity in African American precision medicine we formed ACCOuNT and are proposing a discovery project within cardiovascular pharmacogenomics. In our Discovery project, we hypothesize that through discovery efforts centered on African Americans, we will identify predictive biomarkers of cardiovascular drug response and disease susceptibility that can be investigated in translational outcome studies. We will test this hypothesis with the following aims: 1) Determine genetic predictors of drug response to thrombotic therapy using genome-wide association methodology, 2) Investigate the role of gene expression/splice variants and eQTLs on drug response phenotypes for elucidation of biological mechanisms and genetic regulation of these phenotypes, and 3) Create a publically available and searchable database to house the results of the genomic and transcriptomic studies in African Americans. Through the infrastructure of ACCOuNT we will conduct our discovery efforts with a patient-centered approach that incorporates the input of community partners, frontline physicians and African American patients. We anticipate that these studies will reveal novel SNP associations and gene regulation pathways. Several potential research areas/questions may develop from this work. Our proposed genomics database will serve as needed resource within the pharmacogenomics scientific community, which currently lacks comprehensive genomics and transcriptomic information on African Americans. These new research avenues have the potential of feeding seamlessly into our translational project and pilot projects thus allowing us to leverage our Transdisciplinary Collaborative Center to move implementation of precision medicine in African Americans faster than previous efforts.

药物基因组学旨在鉴定影响个人间个体差异的遗传变异（SNP） 药物反应和不良事件，并具有广泛的临床相关性。它的申请承诺启用 有针对性的药物管理，改善治疗结果并为药物开发提供信息。药物基因组学 见解改善了我们对不良药物背后的基本途径和机制的理解 反应，在美国每年约100,000人死亡，并明显增加 医疗保健费用。 绝大多数药物基因组协会研究，它们是发现领域的驱动因素 精密医学是针对欧洲人口进行的，从而排除了 发现影响药物表型的非裔美国人特异性遗传生物标志物。没有科学 询问这些SNP与药物反应的存在和关联，我们提供精度的能力 七分之一的美国人的药物受到严重阻碍。结束非裔美国人日益增长的荒地差异 精密医学我们成立了帐户，并提出了心血管中的发现项目 药物基因组学。 在我们的发现项目中，我们假设通过以非裔美国人为中心的发现工作，我们将 确定心血管药物反应和疾病易感性的预测生物标志物可以是 在翻译结果研究中进行了研究。我们将以以下目的检验这一假设：1） 使用全基因组关联来确定药物反应对血栓疗法的遗传预测因子 方法论，2）研究基因表达/剪接变体和eqtls对药物反应的作用 阐明生物学机制和这些表型的遗传调节的表型，3） 创建一个可公开可用且可搜索的数据库，以容纳基因组和转录组的结果 非裔美国人的研究。 通过帐户的基础架构，我们将通过以患者为中心的方法进行发现工作 这结合了社区伙伴，一线医生和非裔美国人患者的投入。我们 预计这些研究将揭示新的SNP关联和基因调节途径。一些 这项工作可能会发展潜在的研究领域/问题。我们提出的基因组学数据库将作为 药物基因组学科学界所需的资源，目前缺乏全面 关于非裔美国人的基因组学和转录组信息。这些新的研究途径有 无缝喂食我们的转化项目和试点项目的潜力，从而使我们能够利用我们的 跨学科合作中心转移非洲裔美国人的精密医学实施 比以前的努力快。