Clonal Hematopoiesis in a Biracial Population

项目摘要/摘要 克隆性造血潜能不确定(CHIP)是指选择性扩增来源于 由于获得性体细胞突变而导致的单个造血干细胞。芯片与增加的风险有关 血液病、动脉粥样硬化性心血管疾病(CVD)和死亡率。目前，有有限的 了解导致芯片及其进展的因素。也没有关于监测或 使用芯片治疗个人，以降低他们患白血病或心血管疾病的风险。 在这项建议中，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，社会经济状况，环境暴露，健康行为，如吸烟，酒精， 饮食、锻炼或压力对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(问候)，招收了30,239人 成年人 ≥45年 (44%的黑人，约50%的女性，56%的参与者生活在美国东南部)。我们将使用一种敏感的 靶向测序技术，将有能力检测出现频率较低的芯片突变 与以往大多数研究中使用的完整外显子组测序相比。这项提议的中心目标是 是在随机抽取2500名没有基线心血管疾病的参与者中研究与CHIP相关的因素 确定CHIP的高危人群。广泛的社会人口学、行为和临床数据；以及 炎症、心血管疾病和凝血生物标记物可用于这些参与者的一部分，并将作为 为实现研究目标提供丰富的资源。黑人患上多个芯片相关的风险更高 结果，如低血球计数、心血管疾病和死亡率。这种风险并不能完全解释为 社会人口学或心血管危险因素，我们将探索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距研究。这些科学和训练 计划得到了经验丰富的导师和顾问团队的支持，他们致力于成功实现这一目标 项目和我作为内科科学家的发展。 这项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CHIP和相关结果的理解做出真正的贡献。这个 这项研究的结果将被用作未来评估克隆相关因素的研究的基础 进化(获得新的芯片突变或随着时间的推移克隆大小增加)和相关的不利因素 结果，并最终通知管理的个人与芯片。我建议的研究经验 再加上职业发展计划，导师和优秀的机构支持将为我提供 在血液学和心血管疾病方面发展独立研究事业的资源。

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.