Clonal Hematopoiesis in the Women's Health Initiative

PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related condition in which hematopoietic stem cells in the bone marrow undergo somatic mutations that lead to overgrowth (“clones”) of a genetically distinct subpopulation of blood cells. Evidence is mounting that CHIP is causally related through pro- inflammatory signaling to the occurrence of atherosclerotic cardiovascular disease (CVD) and heart failure (HF). Our preliminary data from the Women’s Health Initiative (WHI) suggests that CHIP may be associated specifically with risk of incident heart failure with preserved ejection fraction (HFpEF), a HF subtype characterized by chronic, low-grade inflammation. Prior studies of CHIP were cross-sectional and limited information is available on behavioral/lifestyle, environmental, and heritable risk factors for CHIP progression. The large (N~161,000), multi- ethnic, prospective WHI, which enrolled post-menopausal women during 1993-1998 is particularly well-suited to address these limitations because of its longitudinal design, availability of extensive exposure and phenotype data, and ongoing surveillance of incident disease/mortality among older women, including HFpEF and HFrEF. In our competing renewal application, we will continue to utilize the unique resources of the WHI, as well as other cohorts and large biobanks, to address several questions of high clinical importance related to the epidemiology of CHIP, heart failure, and its aging-related comorbidities. During the current funding period, a subset of ~7,000 of the original WHI cohort who underwent a subsequent examination and blood sampling in 2012 (ranging from 14 to 19 years after WHI enrollment) as part of the WHI Long Life Study (LLS)-1 exam have undergone deep targeted CHIP sequencing of blood samples collected at two time points, baseline and LLS-1. We plan to expand this longitudinal CHIP resource by sequencing another 5,000 surviving WHI participants using samples collected at the upcoming LLS-2 exam in 2023-2024 including a third time point in 3,000 WHI LLS-1 participants. Together these data motivate further studies to investigate risk factors and specific driver mutations associated with CHIP clonal expansion over a ~30-year period spanning WHI baseline through LL2-2 exams (Aim 1). Validation of any association findings with CHIP progression will be facilitated in additional data sets with WGS using a newly developed in-silico PACER single timepoint approach. In Aim 2, we will perform targeted CHIP sequencing in a large case-cohort of incident HF adjudicated during follow-up (N>5,000 WHI cases and the same number of matched controls) to further assess associations between baseline CHIP and incident heart failure subtypes (HFpEF vs. HFrEF) and replicate findings using additional HF and echo/MRI-based LV function data in other cohorts. In addition, we will explore whether any CHIP-HF associations are modified by other aging-related risk factors or HF comorbidities such as frailty, anemia, or physical activity. Informed by results from Aim 1 and 2, in Aim 3 we will assess causal mediation and underlying mechanisms by which CHIP and CHIP gene subtypes contribute to HFpEF, HFrEF, and other CVD outcomes using an integrative multi-omics approach.