Clonal Hematopoiesis in a Biracial Population

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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.