Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care

不同人群的多基因风险评分 - 连接研究和临床护理

• 批准号: 10658157
• 负责人: Christopher R Gignoux
• 金额: $ 13.2万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10658157
• 关键词: Address; Administrative Supplement; Adoption; Adult; African American; African American population; All of Us Research Program; Architecture; Asian; Awareness; Biological; Blood Pressure; Calibration; Cardiovascular Diseases; Clinical; Collaborations; Data; Diagnosis; Diastolic blood pressure; Disease; Early Intervention; Electronic Health Record; Ensure; Ethnic group; European; Funding; Genes; Genetic; Genetic study; Genomics; Grant; Hispanic; Hypertension; Individual; Latino; Latino Population; Life Expectancy; Life Style; Methodology; Minority Groups; Morbidity - disease rate; Participant; Pathway interactions; Patients; Performance; Phenotype; Population; Population Heterogeneity; Predictive Value; Public Health; Race; Report (document); Research; Resistant Hypertension; Risk; Risk Factors; Structure; Validation; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular risk factor; clinical care; clinical prognostic; clinically relevant; clinically significant; cohort; disability; diverse data; early onset; epidemiology study; ethnic diversity; follow-up; genome wide association study; genomic epidemiology; improved; innovation; insight; interest; lifestyle factors; long-standing disparities; mortality; non-genetic; novel; phenome; polygenic risk score; precision medicine; racial and ethnic disparities; racial diversity; response; risk prediction; risk variant; study population; tool; trait

ABSTRACT This supplement will expand on the currently funded grant R01 HL151152 entitled “Polygenic Risk Scores (PRS) for Diverse Populations - Bridging Research and Clinical Care” through a focused polygenic risk scores analysis of hypertension (HTN) and related traits, an incorporation of All of Us diverse data, and incorporation of lifestyle effects, which were not prioritized in the original R01 application. Cardiovascular disease (CVD) and its risk factors impose major societal burdens and are leading causes of morbidity, mortality, and disability. Recent reports documenting a slowing or reversal of four decades of declining CVD mortality rates motivate an innovative transformation of CVD prevention, diagnosis, and treatment. Genomic research, a cornerstone of precision medicine, offers such a transformation through the application of PRS, the aggregation of risk variants into a single score. However, the vast majority of participants included in the PRS research to-date have been of European ancestry (EA). We have demonstrated that EA-derived PRS are not generalizable to racially and ethnically diverse populations, as EA-derived PRS predict CVD and CVD risk factors with much greater accuracy in EA than in all other race and ethnicity groups. This lack of generalizability reflects differential prediction accuracy and unpredictable bias in the context of population structure that characterizes racially and ethnically diverse populations. Despite these limitations, efforts to commercialize and provide to patients EA- derived PRS are underway, even though the application of EA-derived PRS to diverse populations has the strong potential to exacerbate longstanding racial and ethnic disparities in CVD and CVD risk factors. Research that enables estimation, validation, calibration, and contextualization of PRS in racially and ethnically diverse populations is needed to ensure that all populations reap the benefits of precision medicine. We will utilize data from the Population and Architecture using Genetics and Epidemiology (PAGE) study and aim to fully integrate the All of Us Research Program for independent validation. We propose (i) the creation of unbiased PRS for HTN-related traits (systolic and diastolic blood pressure and HTN) in the ancestrally diverse PAGE study population. The PRS will be validated in the All of Us Research Program; (ii) Contextualization/Performance across key lifestyle factors: Develop and evaluate a lifestyle risk score (LRS) composed of non-genetic clinical and prognostic data to improve predictive performance of PRS. The PRS+LRS will be validated in the All of Us Research Program; and (iii) Clinical Characterization: Evaluate the clinical significance of HTN-related PRS to improve biologic insight of HTN-related diseases using the All of Us research program to prioritize functional follow-up on genes and pathways with greatest clinical impact. We will conduct phenome-wide association (PheWAS) analyses to validate expected hypertension-related associations and detect novel phenotypic associations of potential clinical impact.

摘要