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 本补编将在目前资助的R01 HL151152资助的基础上进行扩展，题为“多基因风险评分 通过集中的多基因风险评分，为不同人群提供(PR)--研究和临床护理之间的桥梁 高血压(HTN)及其相关特征的分析，纳入我们所有不同的数据，并纳入 生活方式的影响，这在最初的R01应用程序中没有优先考虑。心血管疾病(CVD)和 它的风险因素造成了重大的社会负担，是导致发病率、死亡率和残疾的主要原因。 最近的报告记录了40年来心血管疾病死亡率下降的放缓或逆转，这激发了 创新心脑血管疾病预防、诊断、治疗转型。基因组研究，这是 精准医疗通过应用PRS提供了这样一种转变，即风险变量的聚合 变成了一首曲子。然而，到目前为止，参与减贫战略研究的绝大多数参与者都是 欧洲血统(EA)。我们已经证明了EA派生的PR不能推广到种族和 种族多样化的人群，因为EA派生的PR预测心血管疾病和心血管疾病风险因素的风险要大得多 EA的准确性高于所有其他种族和民族群体。这种缺乏概括性反映了差异 预测的准确性和不可预测的偏差在人口结构的背景下，这是种族和 不同种族的人口。尽管存在这些限制，但将EA商业化并提供给患者的努力- 派生的PR正在进行中，尽管EA派生的PR在不同人群中的应用具有 极有可能加剧在心血管疾病和心血管疾病风险因素方面长期存在的种族和族裔差异。研究 这使得在种族和民族多样化的情况下对PR进行估计、验证、校准和情境化 为了确保所有人口都能享受到精准医疗的好处，就需要有更多的人口。我们将利用数据 从人口和建筑使用遗传学和流行病学(PAGE)研究并旨在完全整合 我们所有人的独立验证研究计划。我们建议：(I)设立不偏不倚的责任计划 家族多样性PAGE研究中与HTN相关的特征(收缩和舒张压及HTN) 人口。该方案将在我们所有人的研究方案中得到验证；(Ii)情景/绩效 跨越关键生活方式因素：开发和评估由非遗传临床因素组成的生活方式风险评分(LRS) 和预测数据，以提高PRS的预测性能。该方案将在我们所有人中得到验证 研究计划；和(Iii)临床特征：评估HTN相关的PRS的临床意义 使用我们所有人的研究计划改善HTN相关疾病的生物学洞察力，以确定功能 对临床影响最大的基因和途径进行跟踪。我们将进行全天候的联合 (Phewas)分析以验证预期的高血压相关关联并检测新的表型 潜在临床影响的关联性。