Genetic and social determinants of pharmacological health outcomes in ancestrally diverse populations

祖先不同人群药理健康结果的遗传和社会决定因素

• 批准号: 10578117
• 负责人: Akinyemi Oni-Orisan
• 金额: $ 61.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578117
• 关键词: Address; Adverse drug event; African American population; All of Us Research Program; American; Appointment; Biological; Biology; Biomedical Research; Black race; Characteristics; Clinical; Clinical Pharmacology; Communities; Country; Data; Data Set; Descriptor; Disease; Disease susceptibility; Dose; East Asian; Electronic Health Record; Ensure; Environment; Epigenetic Process; Equity; Ethnic Origin; Ethnic Population; European; Exclusion; Failure; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Goals; Harm Reduction; Health; Healthcare; Heritability; Individual; Infrastructure; Institution; Knowledge; Label; Latino; Latino Population; Life Style; Link; Mexican Americans; Minority Groups; Molecular Genetics; Outcome; Participant; Patients; Pattern; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Phenotype; Population; Population Heterogeneity; Proxy; Puerto Rican; Quantitative Trait Loci; Race; Recommendation; Reporting; Research; Resources; Source; South Asian; Therapeutic; Traction; Underrepresented Populations; United States; United States Food and Drug Administration; United States National Institutes of Health; Variant; Work; Writing; admixture mapping; biobank; cardiovascular disorder epidemiology; care outcomes; clinical practice; cohort; demographics; diverse data; drug efficacy; efficacy outcomes; ethnic difference; ethnic minority; genetic variant; genome sequencing; genome wide association study; genome-wide; genome-wide analysis; health care disparity; improved; insight; medication compliance; medication safety; multidisciplinary; non-genetic; novel; pharmacologic; predicting response; predictive modeling; prevent; racial difference; racial minority; racial population; response; safety outcomes; side effect; social determinants; social factors; social health determinants; sociodemographics; study population; tool; transcriptome; whole genome

PROJECT SUMMARY/ABSTRACT Pharmacogenomics has the potential to dramatically improve health care outcomes, but is currently failing on diversity among its research participants. As a consequence, we do not fully understand all of the factors influencing pharmacogical response in underrepresented populations, including those that contribute to racial/ethnic differences in drug efficacy and safety as reported by Food and Drug Administration (FDA) drug labels. For example, the clinical validity of genetic variants that are common in research participants from historically-excluded populations (e.g., lower proportions of European genetic ancestry), but rare in wellrepresented study populations remains unknown. In addition, gene expression studies have already provided insight into the underlying biology of disease susceptibility for numerous conditions beyond what genome wide association study (GWAS) results alone have discovered, but have not been fully applied to studies of pharmacogenomic discovery. Furthermore, social determinants of health may impact pharmacological drug response from a biological standpoint even after taking into account the effects of these factors on drug adherence, access, and utilization (e.g. social determinants of epigenetics). Addressing this gap in knowledge has the potential to prevent future healthcare disparities that may be exacerbated as the infrastructure to support clinical pharmacogenomics continues to gain traction across health institutions nationwide. Furthermore, elucidation of the genetic and nongenetic contributors to differences in drug response across race/ethnicity will obviate the use of this population descriptor as a proxy for these factors. Pharmacogenomic studies using large, diverse datasets are necessary to ensure that advances in this field benefit individuals equitably. Our primary goal in this project is to identify genetic and social determinants of pharmacological drug response among racial/ethnic minorities. To accomplish this goal, we will leverage data from the Kaiser Permanente Research Biobank (KPRB) and the National Institutes of Health (NIH) All Of Us research program, which are two of the largest electronic health record-linked biobanks in the United States. These cohorts are ideal for the proposed studies because they are large (>400,000 participants each), diverse (>25% racial/ethnic minorities), linked to genome-wide genetic data, and capture social determinants of health. In Aim 1, we will evaluate the relative contribution of genetic ancestry versus social factors on race/ethnicity- based differences in drug efficacy and safety. In Aim 2, we will identify genome-wide polymorphisms predictive of drug effects in historically-excluded populations from large pharmacogenetics studies. In Aim 3, we will use ancestry-specific gene expression results to identify genetic determinants of drug response. The aims will be carried out by an established multidisciplinary team of experts in clinical pharmacology, cardiovascular epidemiology, and molecular genetics. These findings from the current study will help to inform clinical decisions impacting communities historically-excluded from biomedical research.

项目概要/摘要 药物基因组学有潜力显着改善医疗保健结果，但目前尚未实现 研究参与者的多样性。因此，我们并不完全了解所有因素 影响代表性不足的人群的药理反应，包括那些有助于 美国食品和药物管理局 (FDA) 药物报告中药物功效和安全性方面的种族/民族差异 标签。例如，研究参与者中常见的遗传变异的临床有效性 历史上被排除的人群（例如，欧洲遗传血统比例较低），但在 具有代表性的研究人群仍然未知。此外，基因表达研究已经提供 深入了解基因组范围之外的多种疾病易感性的基本生物学 仅关联研究（GWAS）的结果已经发现，但尚未完全应用于以下研究： 药物基因组学的发现。此外，健康的社会决定因素可能会影响药物 即使考虑到这些因素对药物的影响，从生物学角度来看也会产生反应 坚持、获取和利用（例如表观遗传学的社会决定因素）。解决这一知识差距 有潜力防止未来的医疗保健差距，这种差距可能会随着基础设施的支持而加剧 临床药物基因组学继续在全国卫生机构中受到关注。此外， 阐明跨种族/族裔药物反应差异的遗传和非遗传因素将 避免使用该总体描述符作为这些因素的代理。药物基因组学研究使用大量、 为了确保这一领域的进步公平地惠及个人，需要多样化的数据集。 我们在这个项目中的主要目标是确定药理学药物反应的遗传和社会决定因素 少数种族/族裔之间。为了实现这一目标，我们将利用来自 Kaiser Permanente 的数据 研究生物库 (KPRB) 和美国国立卫生研究院 (NIH) 所有人研究计划，这是两个 美国最大的电子健康记录关联生物库。这些群体非常适合 拟议的研究是因为它们规模大（每项都有超过 400,000 名参与者）、多样化（>25% 的种族/族裔少数）， 与全基因组遗传数据相关联，并捕获健康的社会决定因素。 在目标 1 中，我们将评估遗传血统与社会因素对种族/民族的相对贡献—— 基于药物疗效和安全性的差异。在目标 2 中，我们将确定全基因组多态性预测 药物对历史上被排除在大型药物遗传学研究之外的人群的影响。在目标 3 中，我们将使用 祖先特异性基因表达结果可识别药物反应的遗传决定因素。目标将是 由临床药理学、心血管领域的多学科专家团队进行 流行病学和分子遗传学。当前研究的这些发现将有助于为临床决策提供信息 影响历史上被排除在生物医学研究之外的社区。