AS752 - Clonal hematopoiesis of indeterminate potential in aging and exceptional longevity

Investigator Names and Contact Information

Alex Reiner (apreiner@uw.edu) Aladdin Shadyab (aladdinshadyab@health.ucsd.edu)

Introduction/Intent

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition in which somatic mutations in hematologic malignancy-associated genes can be detected in the peripheral blood of otherwise healthy individuals. Research on CHIP has been largely focused on single diseases without consideration of major geriatric syndromes that lead to poor quality of life among older people, such as multimorbidity and mobility impairment. Moreover, the association of CHIP with exceptional longevity has not been studied, as limited cohorts have adequate numbers of long-lived survivors. Further, few studies have leveraged multi-omics to identify molecular mechanisms underlying CHIP incidence or progression, as existing cohorts lack longitudinal CHIP. Currently, a total of 10,000 WHI women have had CHIP measurements performed at baseline through AS628, including ~7,000 with longitudinal CHIP at a second time point ~15 years later (LLS-1). Through the recently released NIA RFA, we propose to obtain 10,854 new CHIP measures (using 1 µg at 100 ng/µl of genomic DNA), which will include: 1) baseline CHIP for all underrepresented groups who survived to ages 90 or older or died before age 90 not part of AS628; all who survived to age 100 not part of AS628; and an additional 500 non-Hispanic White women from the Self Report Cohort who died before 100 not part of AS628 (total: 10,016); 2) the remaining 236 women from LLS-1 not sequenced as part of AS628, who will be sequenced for CHIP at baseline and LLS-1; and 3) baseline CHIP for 366 women from AS712 who do not overlap with AS628. In Aim 1, we will examine associations of baseline CHIP, incident CHIP, and progression of CHIP with multimorbidity, mobility impairment, and total and cause-specific mortality. In Aim 2, we will determine associations of CHIP with exceptional longevity and healthy aging. In Aim 3, we will leverage large-scale epigenomic and 7,000-protein proteomic data to identify molecular signatures associated with baseline CHIP, incidence of CHIP, and progression of CHIP clonal expansion.

We propose the following Specific Aims: Aim 1: Determine the associations of CHIP with aging-related morbidity and mortality outcomes. We will examine associations of baseline CHIP, incidence of CHIP, and progression of CHIP clonal expansion (between baseline and 14-19 years later), including CHIP overall and common CHIP mutation subtypes, with multimorbidity, mobility impairment, and total and cause-specific (CVD-, cancer-, and dementia-related) mortality. Hypothesis: CHIP will be associated with higher risk of multimorbidity, mobility impairment, and mortality. We will explore moderation of these associations by risk factors for CHIP or longevity including race/ethnicity, smoking, epigenetic age, and genetic risk for longevity. Aim 2. Determine the associations of CHIP with exceptional longevity and healthspan at ages 90 and above. We will examine associations of baseline CHIP with (i) survival to ages 90, 95, and 100 and (ii) exceptionally healthy aging, defined as survival to ≥90 years with intact mobility, absence of cognitive impairment, and free of major chronic conditions including cardiovascular disease, cancer, diabetes, and dementia. Hypothesis: CHIP will be associated with reduced longevity and healthspan at ages 90 and above. We will explore moderation by race/ethnicity, smoking, epigenetic age, and genetic risk for longevity. Aim 3: Identify DNA methylation and proteomic signatures associated with baseline CHIP, incidence of CHIP, and progression of CHIP clonal expansion. Hypothesis: Leveraging large-scale epigenomics and 7,000-protein proteomics data, we hypothesize that we will identify DNA methylation and proteomic signatures for CHIP overall and distinct signatures for individual CHIP genes. We will identify differentially methylated positions and plasma proteins that mediate CHIP-outcome associations identified in Aims 1 and 2. Impact. Continuing to build upon the unique resources of the WHI, we plan to address several remaining questions related to the epidemiology of CHIP and age-related phenotypes in older adults.