AS628 – Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Investigator Names and Contact Information

Alex Reiner (apreiner@uw.edu)

Eric Whitsel (eric_whitsel@med.unc.edu)

Introduction/Intent

Clonal hematopoiesis 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. Large-scale next-generation sequencing studies have found such somatic mutations in hematologic malignancy-associated genes (e.g., DNMT3A, TET2, and ASXL1) in blood from healthy subjects, a condition known as clonal hematopoiesis of indeterminate potential (CHIP).  The prevalence of CHIP increases markedly with age, from <1% of the population at age <40; to nearly 10%, 15% and 25% at ages 40-49, 50-59, and 60-69 [1] and to possibly >50% at ages >85. Despite its name, CHIP has been linked to multiple health conditions, including >10-fold higher risk of leukemia/blood cancers, approximately double the risk of cardiovascular disease (CVD), and ~40% higher risk of all-cause mortality.

However, most studies of CHIP are cross-sectional and limited research is available on risk factors for the development, incidence/progression, and consequences of CHIP over long-term follow up. WHI is particularly well-positioned to address these limitations because of its longitudinal design, imbedded clinical trials/ancillary studies, and ongoing surveillance of incident disease/mortality among aging women. To this end, WHI's large size, racial/ethnic diversity, repeated blood collections, and repeated characterization of putative risk factors for CHIP progression over fifteen years in the Long Life Study (LLS) are equally important. Such inherited and acquired risk factors include e.g. aging-related measures (telomere length; epigenetic age), randomized interventions (hormone therapy [HT]; calcium/vitamin D [CaD] supplementation; dietary modification [DM]), and environmental exposures (air/noise pollution; radiation). Indeed, WHI provides an excellent platform for assessing exposure-CHIP-disease associations, including those with incident coronary heart disease (CHD), stroke, heart failure, venous thromboembolism (VTE), diabetes, dementia, cancers (total; site-specific), and mortality (all-cause; cause-specific). We will therefore:

Aim 1. Use 7,800 LLS samples at baseline and approximately fifteen years later to estimate exposure-CHIP associations.  More specifically, we will:

(1a) Estimate associations between prevalent CHIP (at baseline), incidence or progression of CHIP (between baseline and LLS), and putative risk factors for CHIP.

(1b) Assess CHIP heritability and identify novel germline genomic factors that underlie both prevalence and incidence of CHIP.

Aim 2. Use the LLS cohort, additional baseline CHIP data generated in a total of ~17,000 WHI participants, and a nested case-cohort design to estimate CHIP-outcome associations. More specifically, we will:

(2a) Estimate associations between CHIP and incident clinical CVD outcomes, dementia, and mortality

(2b) Estimate associations between CHIP, quantitative hematological (erythrocyte, leukocyte, and platelet) traits, and benign hematologic disorders.

Aim 3. Informed by results from Aims 1 and 2, we will use Mendelian randomization approaches, mediation analyses, and polygenic risk scores to assess causal mediation of exposure-outcome associations by CHIP.

In secondary analyses, we also will explore:

(1) Modification of CHIP-CVD associations estimated in Aim 2a by exposures examined in Aim 1a.

(2) Associations of individual CHIP driver mutations with outcomes in Aims 2a-b.

(3) Differential expression of genes and pathways associated with CHIP in a subset of 1400 participants with whole blood transcriptomic RNAseq data at LLS.