Clonal Hematopoiesis in a Biracial Population

混血人群中的克隆造血

• 批准号: 10444553
• 负责人: Radhika Gangaraju
• 金额: $ 16.4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444553
• 关键词: Address; Adult; Age; Alcohols; Anemia; Anti-Inflammatory Agents; Area; Atherosclerosis; Behavioral; Bioinformatics; Biological Markers; Biometry; Black Populations; Black race; Blood; Blood Cells; Blood specimen; Bone Marrow; Cardiovascular Diseases; Characteristics; Classification; Clinical; Clinical Data; Clinical Pharmacology; Clonal Evolution; Clonal Expansion; Coagulation Process; Coronary heart disease; Coupled; DNA; Development; Development Plans; Diabetes Mellitus; Dyslipidemias; Enrollment; Environmental Exposure; Environmental Risk Factor; Female; Foundations; Frequencies; Funding Mechanisms; Future; Genes; Goals; Grant; Guidelines; Health Disparities Research; Health behavior; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; High Prevalence; Hypertension; Income; Individual; Inflammation; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leukopenia; Light; Mediating; Mentors; Mentorship; Modeling; Modification; Monitor; Mutation; Nature; Neighborhoods; Obesity; Outcome; Participant; Pathogenesis; Pattern; Pharmacology; Phenotype; Physicians; Population; Prevalence; Prevention strategy; Prospective Studies; Prospective cohort study; Race; Reasons for Geographic And Racial Differences in Stroke; Recording of previous events; Research; Research Methodology; Resources; Risk; Risk Factors; Role; Sampling; Scientist; Series; Smoking; Socioeconomic Status; Somatic Mutation; Stress; Stroke; Techniques; Time; Training; United States; adverse outcome; biracial; cardiovascular disorder risk; cardiovascular risk factor; career; career development; cohort; contextual factors; cost; cytopenia; deep sequencing; demographics; diet and exercise; exome sequencing; experience; follow-up; high risk; improved; indexing; leukemia; low socioeconomic status; male; mortality; neighborhood disadvantage; personalized intervention; phenotypic data; programs; prospective; racial difference; racial disparity; residence; risk prediction model; sex; skills; sociodemographics; socioeconomics; success; targeted sequencing; translational scientist; Address; Adult; Age; Alcohols; Anemia; Anti-Inflammatory Agents; Area; Atherosclerosis; Behavioral; Bioinformatics; Biological Markers; Biometry; Black Populations; Black race; Blood; Blood Cells; Blood specimen; Bone Marrow; Cardiovascular Diseases; Characteristics; Classification; Clinical; Clinical Data; Clinical Pharmacology; Clonal Evolution; Clonal Expansion; Coagulation Process; Coronary heart disease; Coupled; DNA; Development; Development Plans; Diabetes Mellitus; Dyslipidemias; Enrollment; Environmental Exposure; Environmental Risk Factor; Female; Foundations; Frequencies; Funding Mechanisms; Future; Genes; Goals; Grant; Guidelines; Health Disparities Research; Health behavior; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; High Prevalence; Hypertension; Income; Individual; Inflammation; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leukopenia; Light; Mediating; Mentors; Mentorship; Modeling; Modification; Monitor; Mutation; Nature; Neighborhoods; Obesity; Outcome; Participant; Pathogenesis; Pattern; Pharmacology; Phenotype; Physicians; Population; Prevalence; Prevention strategy; Prospective Studies; Prospective cohort study; Race; Reasons for Geographic And Racial Differences in Stroke; Recording of previous events; Research; Research Methodology; Resources; Risk; Risk Factors; Role; Sampling; Scientist; Series; Smoking; Socioeconomic Status; Somatic Mutation; Stress; Stroke; Techniques; Time; Training; United States; adverse outcome; biracial; cardiovascular disorder risk; cardiovascular risk factor; career; career development; cohort; contextual factors; cost; cytopenia; deep sequencing; demographics; diet and exercise; exome sequencing; experience; follow-up; high risk; improved; indexing; leukemia; low socioeconomic status; male; mortality; neighborhood disadvantage; personalized intervention; phenotypic data; programs; prospective; racial difference; racial disparity; residence; risk prediction model; sex; skills; sociodemographics; socioeconomics; success; targeted sequencing; translational scientist

PROJECT SUMMARY/ ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) refers to selective expansion of blood cells derived from a single hematopoietic stem cell due to acquired somatic mutations. CHIP is associated with increased risk of hematologic cancer, atherosclerotic cardiovascular disease (CVD) and mortality. Currently, there is limited understanding of the factors that cause CHIP and its progression. There are also no guidelines for monitoring or treatment of individuals with CHIP to mitigate their risk of leukemia or CVD. In this proposal, we seek to understand the factors associated with CHIP. For example, we do not know if race, area of residence, socioeconomic status, environmental exposures, health behaviors such as smoking, alcohol, diet, exercise or stress have any impact on CHIP. We will address these questions in a large prospective study, REasons for Geographic And Racial Differences in Stroke (REGARDS), which enrolled 30,239 adults ≥45 years (44% blacks, ~50% females, and 56% participants living in the southeast United States). We will use a sensitive targeted sequencing technique that will have the ability to detect CHIP mutations present at a low frequency compared to whole exome sequencing used in majority of the previous studies. The central goal of this proposal is to study factors associated with CHIP in a random sample of 2,500 participants without baseline CVD to identify individuals at high risk for CHIP. Extensive sociodemographic, behavioral, and clinical data; as well as inflammation, CVD and coagulation biomarkers are available for a subset of these participants, and will serve as a rich resource to accomplish the aims of the study. Blacks have a higher risk of several CHIP associated outcomes such as low blood counts, CVD and mortality. This risk is not completely explained by sociodemographics or cardiovascular risk factors, and, we will explore the role of CHIP in racial differences of these outcomes. The career development plan includes training in biostatistics and research methodology, bioinformatics analysis, risk prediction modeling and health disparities research. These scientific and training plans are supported by a team of experienced mentors and advisors who are committed to the success of this project and my development as a physician scientist. This proposal will strengthen my skills as a translational researcher, establish an independent research platform, and make a true contribution towards improving our understanding of CHIP and associated outcomes. The results from this study will be utilized as a foundation for future studies assessing factors associated with clonal evolution (acquisition of new CHIP mutations or increase in clone size over time) and associated adverse outcomes, and ultimately inform the management of individuals with CHIP. My proposed research experience coupled with career development plan, mentorship and excellent institutional support will provide me with the resources to develop an independent research career in hematology and CVD.

项目摘要/摘要 不确定电势的克隆造血（CHIP）是指源自源自的血细胞的选择性扩张 由于获得的体细胞突变而引起的单个造血干细胞。芯片与增加的风险有关 血液学癌，动脉粥样硬化心血管疾病（CVD）和死亡率。目前，有限 了解导致芯片及其进展的因素。也没有监视的准则或 治疗芯片的个体以减轻其白血病或CVD的风险。 在此提案中，我们试图了解与芯片相关的因素。例如，我们不知道是否种族 居住区，社会经济状况，环境暴露，诸如吸烟，酒精， 饮食，运动或压力对芯片有任何影响。我们将在一项大型前瞻性研究中解决这些问题， 中风的地理和种族差异的原因（涉及），该差异为30,239 成年人 ≥45岁 （44％的黑人，约50％的女性和56％的参与者居住在美国东南部）。我们将使用敏感的 有针对性的测序技术将能够检测以低频存在的芯片突变 与以前大多数研究中使用的整个外显子组测序相比。该提议的核心目标 是在2500名参与者的随机样本中研究与CHIP相关的因素，而没有基线CVD 确定芯片高风险的人。广泛的社会人口统计学，行为和临床数据；也 这些参与者的炎症，CVD和凝结生物标志物可用，并将作为 实现研究目标的丰富资源。黑人与几个芯片相关的风险更高 诸如血液计数，CVD和死亡率之类的结果。这种风险并不能完全解释 社会人口统计学或心血管危险因素，我们将探讨芯片在种族差异中的作用 这些结果。职业发展计划包括生物统计学和研究方法的培训， 生物信息学分析，风险预测建模和健康差异研究。这些科学和训练 计划得到了一个经验丰富的导师和顾问团队的支持，他们致力于成功 项目和我作为物理科学家的发展。 该建议将加强我作为翻译研究人员的技能，建立一个独立的研究平台， 并为提高我们对芯片和相关结果的理解做出真正的贡献。这 这项研究的结果将被用作未来研究的基础，以评估与克隆相关的因素 进化（获取新芯片突变或随着时间的推移增加克隆的规模）和相关的广告 结果，并最终告知管理芯片个人的管理。我提出的研究经验 再加上职业发展计划，指导和出色的机构支持将为我提供 发展血液学和CVD独立研究职业的资源。