Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of a clonally expanded hematopoietic stem cell caused by a leukemogenic mutation in individuals without evidence of hematologic malignancy, dysplasia, or cytopenia. CHIP is associated with a 0.5-1.0% risk per year of leukemia. Remarkably, it confers a two-fold increase in cardiovascular risk independent of traditional risk factors. Roughly 80% of patients with CHIP have mutations in epigenetic regulators DNMT3A, TET2, ASXL1, DNA damage repair genes PPM1D, TP53, the regulatory tyrosine kinase JAK2, or mRNA spliceosome components SF3B1, and SRSF2. CHIP is associated with a pro-inflammatory state that has been linked to coronary artery disease, myocardial infarction, and venous thromboembolic disease, as well as prognosis among those with aortic stenosis and heart failure. Heritable and acquired risk factors are associated with increased CHIP prevalence, including germline variation, age, unhealthy lifestyle behaviors (i.e. smoking, obesity), inflammatory conditions, premature menopause, HIV and exposure to cancer therapies. This review aims to summarize emerging research on CHIP, the mechanisms underlying its important role in propagating inflammation and accelerating cardiovascular disease, and new studies detailing the role of associated risk factors and co-morbidities that increase CHIP prevalence.

Keywords: ASCVD; Aortic stenosis; CHIP; Cardio-oncology; Heart failure; Inflammation.

Figure 1:. CHIP associates with an altered inflammatory state, elevating cardiovascular risk

The acquisition of driver mutations (in DNMT3A, TET2, and JAK2 shown as a selection here) leads to clonal hematopoiesis of indeterminate potential (CHIP), which induces an altered inflammatory state that is associated with an increased risk of atherosclerosis, poorer outcomes in aortic stenosis and heart failure, and enhanced thrombogenesis. HSC= hematopoietic stem cell, NET = neutrophil extracellular traps (created with Biorender.com)

Figure 2:. Selected hazard ratios (HR) for CHIP and incident coronary heart disease are of similar magnitude to traditional risk factors

(A) HR with 95% CI for incident coronary heart disease adjusted for age, sex, HTN, HLD, smoking, obesity, diabetes among Jackson Heart Study & FUSION participants, Summarized data from Jaiswal et al 2014 [4] (B) HR with 95% CI for incident coronary heart disease adjusted for age, sex, HTN, total and HDL cholesterol, triglycerides, smoking, and type 2 diabetes among BioImage, MDC (CHIP) and a fixed-effects meta-analysis for each gene (incorporating BioImage, MDC, JHS/Fusion/FHS). Summarized data from Jaiswal et al 2017 [7]