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.

项目总结/摘要 药物基因组学有潜力极大地改善医疗保健结果，但目前在 研究参与者的多样性。因此，我们不能完全理解所有的因素， 在代表性不足的人群中影响药理学反应，包括导致 美国食品药品监督管理局（FDA）药物安全性报告的药物疗效和安全性的种族/民族差异 标签。例如，遗传变异的临床有效性在研究参与者中很常见， 历史上被排除在外的人群（例如，欧洲遗传祖先的比例较低），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了 深入了解疾病易感性的潜在生物学， 关联研究（GWAS）的结果已经发现，但尚未完全应用于研究 药物基因组学发现此外，健康的社会决定因素可能会影响药理学药物 从生物学角度来看，即使考虑到这些因素对药物的影响， 坚持，访问和利用（例如表观遗传学的社会决定因素）。弥补这一知识差距 有可能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获得牵引力。此外，委员会认为， 阐明不同人种/种族间药物应答差异的遗传和非遗传因素， 禁止使用这一人口描述符作为这些因素的替代。药物基因组学研究， 为了确保这一领域的进展公平地惠及个人，需要有各种数据集。 我们在这个项目中的主要目标是确定药物反应的遗传和社会决定因素 种族/少数民族。为了实现这一目标，我们将利用Kaiser Permanente的数据 研究生物库（KPRB）和美国国立卫生研究院（NIH）所有的我们研究计划，这是两个 美国最大的电子健康记录相关生物银行。这些群体是理想的 建议的研究，因为它们是大的（> 400，000参与者），多样化（>25%的种族/少数民族）， 与全基因组遗传数据相关联，并捕捉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 从大型药物遗传学研究中排除的历史人群中的药物效应。在目标3中，我们将使用 祖先特异性基因表达结果，以确定药物反应的遗传决定因素。目标将是 由临床药理学、心血管和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 影响了历史上被排除在生物医学研究之外的社区。