Clonal Hematopoiesis in a Biracial Population

项目总结/摘要 不确定潜能的克隆性造血（CHIP）是指来源于造血干细胞的血细胞的选择性扩增。 单个造血干细胞由于获得性体细胞突变。CHIP与以下风险增加相关： 血液学癌症、动脉粥样硬化性心血管疾病（CVD）和死亡率。目前， 了解导致CHIP及其进展的因素。也没有监测或 CHIP患者的治疗，以减轻他们患白血病或CVD的风险。 在本提案中，我们试图了解与CHIP相关的因素。例如，我们不知道种族， 居住地区、社会经济地位、环境暴露、健康行为，如吸烟、饮酒， 饮食、运动或压力对CHIP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（REGARDS），该研究招募了30，239人 成年人 ≥45岁 (44%的黑人，约50%的女性，56%的参与者生活在美国东南部）。我们将使用敏感的 一种靶向测序技术，能够检测低频率存在的CHIP突变 与大多数先前研究中使用的全外显子组测序相比。这项提议的中心目标是 在随机抽样的2,500名没有基线CVD的参与者中研究CHIP相关因素， 识别CHIP高风险个体。广泛的社会人口统计学、行为和临床数据;以及 炎症、CVD和凝血生物标志物可用于这些参与者的子集，并将作为 丰富的资源来实现研究的目标。黑人患几种CHIP相关疾病的风险更高 结果，如低血细胞计数，CVD和死亡率。这种风险并不能完全解释为 社会人口统计学或心血管危险因素，我们将探讨CHIP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方面的培训， 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 计划由经验丰富的导师和顾问组成的团队提供支持，他们致力于使计划取得成功。 项目和我作为一名医生科学家的发展。 这个建议将加强我作为一个翻译研究者的技能，建立一个独立的研究平台， 并为提高我们对CHIP和相关成果的理解做出真正的贡献。的 这项研究的结果将作为未来研究的基础，评估与克隆相关的因素。 进化（随着时间的推移获得新的CHIP突变或克隆大小增加）和相关的不良反应 结果，并最终告知CHIP个人的管理。我的研究经验 再加上职业发展计划，导师和优秀的机构支持，将为我提供 资源，以发展血液学和CVD的独立研究事业。

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.