Understanding dynamics and phenotypic consequences of clonal hematopoiesis caused by mosaic chromosomal alterations

About This Grant

PROJECT SUMMARY This NIH F30 grant proposal investigates how somatic mutations in hematopoietic stem cells (HSCs) contribute to aging-related diseases through clonal expansion of mutated blood cells. This phenomenon, called clonal hematopoiesis, becomes more common as individuals age, affecting over 10% of in people over 60 years old. This study focuses on mosaic chromosomal alterations (mCAs), large-scale mutations that are under-studied compared to smaller mutations like clonal hematopoiesis of indeterminate potential (CHIP). mCAs are linked to lymphoid malignancies and infection susceptibility due to lymphoid-biased differentiation, while CHIP correlates with cardiovascular diseases and myeloid malignancies through myeloid-biased differentiation. I hypothesize that mCA expansion is determined by individual factors rather than mCA genetic change and that clones with greater expansion rates will have increased disease risk. Aim 1 examines the influence of mCA characteristics and environmental factors on clonal expansion rates using longitudinal blood samples from 30,000 individuals in Vanderbilt’s BioVU genomic and clinical biobank. Using longitudinal mCA trajectories, I will quantify the contribution of the mCA mutation and individual characteristics (e.g., age, sex, BMI, smoking, type 2 diabetes, lipoprotein levels) to clonal expansion rate and build a predictive model for mCA clonal expansion. My working hypothesis for Aim 1 is that mCA expansion varies widely among individuals with the same mCA and thus modifiable lifestyle exposures are major contributors to clonal expansion rate. The longitudinal samples in BioVU will not be sufficient to test genetic and phenotypic associations with clonal expansion rate. Therefore, Aim 2 expands the study to detect mCAs in > 1 million individuals across various genomic biobanks with single blood draws (i.e., NHLBI TOPMed, NIH All of Us, UK Biobank, and BioVU). To determine mCA clonal expansion rate from a single timepoint, I will apply Passenger-Approximated Clonal Expansion Rate (PACER), which estimates mCA expansion rate from a single blood draw to build upon my measured mCA analysis by two orders of magnitude. A genome-wide association study and a phenome-wide association study will be conducted to identify germline variants and phenotypic correlations related to mCA clonal expansion rates. My working hypothesis for Aim 2 is that 1) certain germline variants predispose individuals to faster mCA growth and 2) specific disease phenotypes, including chronic lymphocytic leukemia and infection susceptibility, are associated with faster mCA clonal expansion rate. This research aims to significantly enhance our understanding of mCA clonal expansion, addressing a fundamental biological mechanism of aging to prevent multiple diseases. Collectively, these insights will contribute to mCA risk prediction models and highlight potential biological pathways or lifestyle strategies to slow mCA expansion.