Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease

Abstract

Chronologic age is the dominant risk factor for coronary artery disease but the features of aging promoting coronary artery disease are poorly understood. Advances in human genetics and population-based genetic profiling of blood cells have uncovered the surprising role of age-related subclinical leukemogenic mutations in blood cells, termed “clonal hematopoiesis of indeterminate potential,” in coronary artery disease. Such mutations typically occur in DNMT3A , TET2 , ASXL1 , and JAK2 . Murine and human studies prioritize the role of key inflammatory pathways linking clonal hematopoiesis with coronary artery disease. Increasingly larger, longitudinal, multiomics analyses are enabling further dissection into mechanistic insights. These observations expand the genetic architecture of coronary artery disease, now linking hallmark features of hematologic neoplasia with a much more common cardiovascular condition. Implications of these studies include the prospect of novel precision medicine paradigms for coronary artery disease.

Inflammasomes and Atherosclerosis: a Mixed Picture

“…91,92 CH increases in frequency with aging and may partly explain why aging is a potent CVD risk factor. 93 CH increases the risk of both myeloid malignancy and CVD but the latter has a much broader impact on human health. 94 The NLRP3 inflammasome promotes accelerated atherosclerosis in chimeric mice modeling TET2 CH, 57 while the AIM2 inflammasome aggravates atherosclerosis in JAK2 VF CH.…”

Clonal Hematopoiesis and Coronary Artery Disease—A Deep Connection

“…Clonal hematopoiesis, often referred to as clonal hematopoiesis of indeterminate potential (CHIP), is gaining recognition as an important and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). 1,2 This condition results from the acquisition of certain somatic mutations in hematopoietic stem cells that confer a competitive advantage to the mutated cells, leading to their clonal expansion throughout the hematopoietic system and its progeny, which includes immune cells. Therefore, individuals with clonal hematopoiesis harbor a substantial proportion of immune cells bearing the acquired mutation, a circumstance that can profoundly influence inflammatory responses that are at the center of the pathophysiology of atherosclerosis.…”

“…Therefore, individuals with clonal hematopoiesis harbor a substantial proportion of immune cells bearing the acquired mutation, a circumstance that can profoundly influence inflammatory responses that are at the center of the pathophysiology of atherosclerosis. [1][2][3] In this issue of JAMA Cardiology, Zhao and colleagues 4 enrich our understanding of this emerging cardiovascular risk factor by reporting the effects of clonal hematopoiesis on incident coronary artery disease (CAD)-related events in a large East Asian population that was free of cardiovascular disease at baseline. The authors conducted deep targeted sequencing of 90 genes related to clonal hematopoiesis in 6181 participants in the Prediction for ASCVD Risk in China (China-PAR) project (median age, 53.8 years; approximately 50% women).…”

“…Putting together larger high-sensitivity sequencing datasets will be required to further understand the effects of mutations in other CHIP genes linked to ASCVD in prior research, such as TP53 or JAK2. 1,2 To grasp the added value of the study in a field that has become a hot topic of research in recent years, the authors' findings must be interpreted in light of currents gaps in our knowledge of the relationship between CHIP and CAD. First, and perhaps most importantly, the deep coverage of the targeted sequencing strategy used by the authors offers valuable new insights into the threshold of mutant clone size that defines clinically relevant CHIP.…”

“…Previous human genetic evidence linking CHIP to CAD was derived from the analysis of whole-exome sequencing (WES) datasets from large biobank studies. 1,2 While this approach has expedited progress of the field, it provides limited sensitivity to detect somatic mutations with low VAF. Considering this limitation, there was a substantial body of evidence supporting the association between CHIP with a VAF of 10% or greater (>20% mutant blood cells) and an increased risk of CAD.…”