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Clonal hematopoiesis may be a modifiable risk factor for atherosclerotic cardiovascular disease

Aging is associated with an increased incidence of cancer and cardiovascular disease.
Researchers recently used whole-exome sequencing data to identify a common, age-related disorder marked by an expansion of hematopoietic clones carrying recurrent somatic mutations, most frequently loss-of-function alleles in the genes DNMT3A, TET2, and ASXL1.
These mutations, which are also common in the myelodysplastic syndrome and acute myeloid leukemia, provide a selective advantage to the hematopoietic stem cells in which they occur and are detectable as clones in peripheral-blood samples because the mutated stem cells maintain the ability to differentiate into circulating granulocytes, monocytes, and lymphocytes.
Such clones rarely accumulate in persons younger than 40 years of age, but they become more common among older persons, with more than 10% of persons older than 70 years of age carrying such a mutation.
Carriers of these mutations have 10 times the risk of a hematologic cancer as do those without such mutations.

On the basis of these findings, researchers provisionally defined persons carrying such mutations in the absence of any other hematologic abnormalities as having clonal hematopoiesis of indeterminate potential ( CHIP ).

An exploratory analysis revealed that persons with CHIP are at increased risk for death from any cause and, surprisingly, for coronary heart disease.
Although traditional risk factors for coronary heart disease ( e.g., hypercholesterolemia, type 2 diabetes, hypertension, and smoking ) account for a large proportion of the risk, many persons with atherosclerosis or coronary heart disease do not have established risk factors,which suggests that unknown factors may also contribute to atherosclerosis and its complications.

In a study, researchers tested the hypothesis that CHIP contributes causally to atherosclerotic cardiovascular>
In four distinct studies involving human participants, researchers found that somatic mutations leading to CHIP had significant associations with the risk of coronary heart disease or early-onset myocardial infarction.
In a murine model of atherosclerosis, the loss of Tet2 function in hematopoietic cells accelerated atherogenesis.

The results of the study have supported several conclusions.

First, the relationship between CHIP and coronary heart disease appears to be a causal one. Experimental manipulation of one of the genes that is most frequently mutated in CHIP ( Tet2 ) worsened atherosclerosis in mice. In humans, coronary events increased in relation to clone size, and there was also a dose–response relationship between clone size and atherosclerosis on imaging.

Second, mutations in multiple CHIP-associated genes were linked to coronary heart disease. These mutations may increase the risk of coronary events owing to altered transcriptional output of macrophages.
These cells mediate many inflammatory responses and prominently populate atherosclerotic plaques.
In support of this model, researchers found that loss of Tet2 augmented the expression of inflammatory chemokines in macrophages that were exposed to native LDL, an effect that is similar to that in Tet2-deficient macrophages that were exposed to bacterial endotoxin.

Previous studies have shown that CXC chemokine interaction with the receptor CXCR2 can mediate firm monocyte adhesion to inflamed endothelium and that this interaction promotes atherogenesis.

Researchers have proposed that a major consequence of TET2 deficiency in tissue macrophages is the enhanced recruitment of monocytes and other blood cells to peripheral sites, including the arterial intima, because of elevated expression of CXC chemokines.
Several organs of mice lacking hematopoietic Tet2 harbored large leukocyte aggregates, and TET2 mutations in humans were associated with increased plasma levels of interleukin-8.
A recent study also identified augmented Il1b and inflammasome activation as a major mediator of atherosclerosis in mice with hematopoietic Tet2 deficiency. It is unclear which particular inflammatory mediators predominate in driving atherosclerosis associated with TET2 deficiency and whether mutations in DNMT3A, ASXL1, and JAK2 also influence the risk of coronary events by means of increased inflammation, issues that invite further experimentation.

An alternative explanation for the observed association is that CHIP-associated mutations provide a proliferative advantage to hematopoietic progenitors and a consequent increase in circulating myeloid cells.
Elevations in levels of peripheral-blood granulocytes and monocytes have been linked to coronary outcomes in the general population, whereas persons with JAK2-mutated myeloproliferative neoplasms are at increased risk for venous and coronary thrombosis, according to the degree of leukocytosis.
However, nearly all persons with clonal hematopoiesis caused by mutations in DNMT3A, TET2, and ASXL1 have a normal white-cell count and differential,and JAK2 mutations account for only a small percentage of CHIP.
Furthermore, mice that lacked hematopoietic Tet2 had normal blood counts in the study and in previous studies.
Nonetheless, researchers cannot fully rule out a role for leukocytosis in human coronary heart disease, since CHIP could lead to a myeloproliferative state over several years.

In conclusion, the data support the hypothesis that somatic mutations in hematopoietic cells contribute to the development of human atherosclerosis.
Researchers have proposed that clonal hematopoiesis may be a modifiable risk factor, perhaps through the use of cholesterol-lowering medications or targeting of specific inflammatory pathways. ( Xagena )

Source: The New England Journal of Medicine, 2018