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. Large-scale, next generation sequencing studies have established that CHIP is a proinflammatory condition common among older adults, and that CHIP is a risk factor for future occurrence of hematologic cancers, cardiovascular disease, and all-cause mortality. The most commonly mutated genes associated with CHIP (DNMT3A, TET2 and ASXL1) are key epigenetic regulators involved in DNA methylation and chromatin remodeling. Our published work has identified associations of CHIP with age-related diseases, germline genetic variants, and non-genetic factors (e.g., body mass index, smoking). However, 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 of CHIP clonal expansion, as existing epidemiologic cohorts largely lack longitudinal CHIP collected throughout the life course. 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 including race/ethnicity, smoking, and epigenetic age.

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, and epigenetic age.

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.