Why does CHIP lead to cardiovascular disease? The answers are becoming clearer

Siddhartha Jaiswal, MD, PhD

Oct. 3, 2023

By Christopher Vaughan

Some people, as they age, get a condition in which mutant blood stem cells gain a competitive advantage over other blood stem cells and begin to take over. People with this condition, called CHIP (clonal hematopoiesis of indeterminate potential), will harbor a clone of blood and immune cells derived from a single mutant stem cell. Previous research has shown that people with CHIP may seem perfectly healthy, and yet are at higher risk for atherosclerosis, blood cancers, and other diseases.

Institute researchers have now shown why people with CHIP may be at higher risk for some cardiovascular diseases. Assistant Professor of Pathology Siddhartha Jaiswal, MD, PhD and his colleagues have discovered that the two most common mutations in CHIP, in the genes TET2 and DNMT3A, can both induce similar inflammatory programs in mice. Inflammation has long been associated with the atherosclerosis disease process, providing an explanation for a likely mechanism connecting mutations in these two genes and cardiovascular disease.

“This was surprising, because these two genes have opposite effects biochemically,” Jaiswal said. “DNMT3Aencodes an enzyme that promotes the methylation of methylcytosine, while TET2 encodes an enzyme that initiates the demethylation of methylcytosine.”

The research was published the journal Nature Cardiovascular Research. Jaiswall is senior author. Philipp J. Rauch, MD, an instructor in Medicine at Harvard Medical School, and  Stanford medical student Jayakrishnan Gopakumar are first authors.

The researchers tested a few possible ways that the loss of a functional DNMT3 might promote atherosclerosis. They had previously shown that stem cells with TET2 mutations gave rise to macrophages that promoted inflammation when exposed to high levels of LDL cholesterol (the “bad” cholesterol). In the end, they were able to show that macrophages derived from blood stem cells with mutant DNMT3A also promoted inflammatory processes.

“So even though these two genes have opposite effects on a basic biochemical level, the effects of the loss of function in either gene converge at the cellular level to produce a common, pro-inflammatory effect on cardiovascular tissues,” Rauch said.

Such pro-inflammatory effects might be part of the reason CHIP is associated with other diseases, the researchers note. Patients with heart failure who have mutations in TET2 or DNMT3A face a far worse prognosis than those who don’t. CHIP associated with DNMT3A mutations also raises the risk for osteoporosis. The researchers hope that by understanding some of the underlying mechanisms by which CHIP acts to raise disease risk, they might be able to come up with interventions to reduces those risks.

The work was supported by the National Institutes of Health (P01CA066996, P50CA206963 and R01HL082945, DP2-HL157540, 1R01HL134892, 1R01HL163099-01, 5U54CA20997105, 5DP5OD01982205, 1R01CA24063801A1, 5R01AG06827902, 5UH3CA24663303, 5R01CA22952904, 1U24CA22430901, 5R01AG05791504 and 5R01AG05628705), the Department of Defense (grant no. W81XWH2110143), the Bill and Malinda Gates Foundation, the Cancer Research Institute, the Parker Center for Cancer Immunotherapy, the Breast Cancer Research Foundation, the Ludwig Center for Cancer Stem Cell Research, Leukemia and Lymphoma Society, Knight Initiative for Brain Resilience, the Leducq Foundation, the Burroughs Wellcome Fund, EvansMDS Foundation, the Howard Hughes Medical Institute, the EvansMDS Foundation, the John R. Svenson Endowed Fellowship,  the Japan Society for the Promotion of Science Overseas Fellowship, John S. LaDue Memorial Fellowship in Cardiology, the American Society of Hematology Research Training Grant for Fellows, the American College of Cardiology Merck Fellowship in Cardiovascular Disease and the Metabolic Syndrome, the RRM Charitable Fund and the Simard Fund.