The presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral-blood cells was associated with nearly a doubling in the risk of coronary artery disease (CAD) in humans in a study published June 21 in the New England Journal of Medicine. Accelerated atherosclerosis was also noted in mice.

Researchers used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells. From there, such presence was associated with CAD using samples from four case-control studies consisting of 4,726 total participants with CAD and 3,529 controls. Additionally, researchers assessed atherosclerosis in mice by transplanting bone marrow from TET2 control mice or heterozygous or homozygous knockout mice into atherosclerosis-prone mice bred to have a knockout mutation for the gene encoding low-density lipoprotein receptor.

Results from two prospective cohorts in a nested case-control analysis showed CHIP carriers had a 1.9 times greater risk of coronary heart diseases as noncarriers. In two retrospective case-control cohorts, participants with CHIP were at 4.0-times greater risk of myocardial infarction as noncarriers. Researchers also noted that CHIP carriers with DNMT31, TET2, ASXL1 and JAK2 mutations were at increased risk for coronary artery calcification, which may increase the risk of coronary events “owing to altered transcriptional output of macrophages.” In the mice cohort, the hypercholesterolemia-prone mice transplanted with bone marrow from homozygous or heterozygous TET2 knockout mice had bigger atherosclerotic lesions in the aortic root and aorta than control mice.

Researchers note their results support several conclusions, including that “the relationship between CHIP and coronary heart disease appears to be a causal one.” They suggest that CHIP could be a modifiable risk factor, possibly through using cholesterol-lowering medications or targeting of specific inflammatory pathways.

In a related editorial comment, John F. Keaney Jr., MD, FACC, writes that the study findings “should prompt a discourse about studying the use of anti-inflammatory agents in patients with CHIP to limit the most common cause of death in these patients – cardiovascular disease.” At the same time, he also writes that important questions also remain, including “whether CHIP or specific mutations in CHIP driver genes have an effect on other traditional risk factors for cardiovascular disease in a way that might also promote atherosclerosis.”

Keywords: Aorta, Atherosclerosis, Blood Cells, Bone Marrow, Cause of Death, Cholesterol, Coronary Artery Disease, Exome, Hematopoiesis, Hypercholesterolemia, Lipoproteins, LDL, Macrophages, Mice, Mice, Knockout, Mutation, Myocardial Infarction, Prospective Studies, Receptors, LDL, Research Personnel, Risk Factors

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