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: 10381373
• 负责人: Christopher R Gignoux
• 金额: $ 8.38万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2022-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381373
• 关键词: Adult; African American; Architecture; Awareness; Biological; Blood Pressure; Cardiovascular Diseases; Colorado; Data; Development; Diagnosis; Disease; Early Intervention; Electronic Health Record; Ensure; Ethnic Origin; Ethnic group; European; Fred Hutchinson Cancer Research Center; Funding; Genetic Determinism; Genetic Risk; Genetic study; Genomics; Grant; High Prevalence; Hispanics; Hypertension; Individual; Latino; Life Style; Link; Love; North Carolina; Parents; Participant; Performance; Population; Population Heterogeneity; Positioning Attribute; Premature Mortality; Prevalence; Prevention; Public Health; Publications; Race; Research; Resistant Hypertension; Risk; Risk Factors; Training; Universities; biobank; cardiovascular disorder risk; clinical care; clinically significant; cohort; disorder risk; early onset; genomic epidemiology; hypertension treatment; improved; insight; multi-ethnic; non-genetic; polygenic risk score; precision medicine; prognostic; racial and ethnic; racial and ethnic disparities; risk variant; skills; study population; trait

PROJECT SUMMARY Hypertension is a major public health burden in the US, due to its high prevalence among adults (~108 million, 45%) and strong association with cardiovascular disease (CVD) and premature mortality. Compared to other racial/ethnic groups, African-Americans have higher hypertension prevalence, higher mean blood pressure (BP), earlier onset of hypertension, and a greater likelihood of developing treatment-resistant hypertension. In addition, rates are increasing among Hispanic/Latinos, who have lower rates of hypertension awareness, treatment, and control. Advances in genomic research create opportunities for precision medicine to improve prevention, diagnosis, and treatment of hypertension. Polygenic risk scores (PRS) that aggregate genetic risk variants into a score help predict disease risk. Growing evidence demonstrates that PRS may add value beyond traditional risk factors for identifying individuals at increased risk for CVD. Despite their promise, however, current PRS are biased in populations historically underrepresented in genetic studies. Despite the increased risk of hypertension in African-American and Hispanic/Latino populations, PRS originally trained on European ancestry (EA) participants may not serve these populations. Indeed, applying EA-derived PRS to racially/ethnic diverse populations has the strong potential to exacerbate longstanding racial/ethnic disparities in CVD and hypertension. Thus, PRS derived in multi-ethnic populations are needed to ensure that all will benefit from genomic research advances regardless of their race/ethnicity or ancestral heritage. The proposed research will: 1) Develop and evaluate PRS for hypertension related traits in the large and racially/ethnically diverse Population Architecture using Genomics and Epidemiology (PAGE) study population, 2) Extend the multi-ethnic PRS through integration of a lifestyle risk factor score (LRS) composed of non-genetic clinical and prognostic data to improve predictive performance of PRS, and 3) Evaluate the clinical significance of hypertension related PRS in electronic health records (EHRs) to improve biologic insight of hypertension-related diseases. These study aims are nested within the parent study, Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care, R01HL151152, a collaborative effort between the University of North Carolina at Chapel Hill, the Fred Hutchinson Cancer Research Center Seattle, and the University of Colorado Denver, using high-quality, harmonized, and centrally available data from a network of cohorts and biobanks with linked EHRs, including over 1.5M non-European ancestry participants. Through the proposed Postdoctoral Supplement, Dr. Love will gain training in developing, validating, and assessing the clinical significance of hypertension related PRS in multiethnic populations, lifestyle and genetic determinants of hypertension, and professional development. Skills and findings obtained from the completion of the training and research aims of this proposal will result in scientific presentations and publications, preliminary data to successfully compete for grant funding, and uniquely position Dr. Love for the study of genetic and lifestyle determinants of CVD.

项目摘要 高血压是美国主要的公共卫生负担，因为其在成年人中的高患病率（约1.08亿， 45%），并与心血管疾病（CVD）和过早死亡密切相关。相比其他 种族/民族群体，非洲裔美国人有较高的高血压患病率，较高的平均血压（BP）， 高血压发病较早，且发生难治性高血压的可能性更大。此外，本发明还提供了一种方法， 西班牙裔/拉丁美洲人的高血压发病率正在上升，他们的高血压知晓率、治疗率和 控制基因组研究的进展为精准医学创造了机会，以改善预防， 诊断和治疗高血压。多基因风险评分（PRS）将遗传风险变异汇总为 得分有助于预测疾病风险。越来越多的证据表明，减贫战略可以增加传统减贫战略以外的价值。 识别CVD风险增加的个体的风险因素。然而，尽管有这些承诺，目前的减贫战略仍是 在遗传学研究中被低估的人群中存在偏见。尽管高血压风险增加 在非洲裔美国人和西班牙裔/拉丁裔人口中，PRS最初接受欧洲血统培训（EA） 参与者可能无法为这些人群服务。事实上，将从环境评估得出的减贫战略应用于种族/族裔多样性， 人群有很大的可能加剧CVD中长期存在的种族/民族差异， 高血压因此，需要在多族裔人口中制定减贫战略，以确保所有人都能受益于 基因组研究的进展与其种族/民族或祖先遗产无关。拟议的研究将： 1)在大型和种族/民族多样化人群中制定和评价高血压相关性状的PRS 使用基因组学和流行病学（PAGE）研究人群的架构，2）扩展多种族PRS 通过整合由非遗传临床和预后数据组成的生活方式风险因素评分（LRS）， 提高PRS的预测能力; 3）评价高血压相关PRS的临床意义， 电子健康记录（EHR），以提高高血压相关疾病的生物学洞察力。这些研究目的 嵌套在母研究中，不同人群的多基因风险评分-桥接研究和 临床护理，R 01 HL 151152，北卡罗来纳州查佩尔山大学， 弗雷德哈钦森癌症研究中心西雅图，和科罗拉多丹佛大学，使用高质量， 来自具有相关EHR的队列和生物库网络的统一且集中可用的数据，包括 超过150万非欧洲血统的参与者。通过拟议的博士后补充，爱博士将 获得开发、验证和评估高血压相关PRS临床意义的培训， 多种族人群、高血压的生活方式和遗传决定因素以及职业发展。技能 从完成本建议的培训和研究目标中获得的结果将导致科学的 演讲和出版物，初步数据，成功地竞争赠款资金，并独特的地位 博士热爱研究心血管疾病的遗传和生活方式决定因素。