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Cardiovascular Disease Risk Is Increased by Aging-Related Mutations in Blood Cells

NEW YORK (GenomeWeb) – Mutations that crop up in blood cells due to aging contribute to cardiovascular disease risk, according to a new study.

Such mutations lead certain blood stem cells to become much more common than others — a state dubbed clonal hematopoiesis of indeterminate potential, or CHIP — and, in previous work, CHIP has been linked to an increased risk of blood cancer and death from heart attack or stroke.

Researchers from the Broad Institute and elsewhere drew on four case-control studies totaling more than 8,000 people to determine whether CHIP was also associated with coronary heart disease. As they reported in the New England Journal of Medicine yesterday, the researchers found that CHIP carriers had nearly double the risk of developing coronary heart disease as non-carriers. In a series of mouse models, they further linked CHIP mutations to increased atherosclerosis and expression of inflammatory molecules.

"A key finding from this study is that somatic mutations are actually modulating risk for a common disease, something we haven't seen other than in cancer," first author Siddhartha Jaiswal, a pathologist at Massachusetts General Hospital, said in a statement. "It opens up interesting questions about other diseases of aging in which acquired mutations, in addition to lifestyle and inherited factors, could modulate disease risk."

Jaiswal and his colleagues obtained 1,010 blood samples for whole-exome sequencing from people with and without coronary heart disease from the BioImage and the Malmö Diet and Cancer cohorts. The Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group and the Pakistan Risk of Myocardial Infarction Study cohorts had already undergone whole-exome sequencing.

They identified CHIP carriers based on variants in a set of 74 genes that are often mutated in myeloid cancers. From the BioImage and MDC samples, the researchers found that the most common somatic mutations were in the DNMT3A, TET2, and ASX1 genes.

Additionally, among the BioImage and MDC participants, the researchers reported that CHIP carriers had a 1.9 times higher risk of coronary heart disease than non-carriers. Similarly, they reported that in the ATVB and PROMIS cohorts, CHIP was associated with increased odds of early-onset myocardial infarction.

In the BioImage and MDC cohorts as well as three US-based cohorts without selection for coronary events, the researchers found that mutations within the DNMT3A, TET2, and ASXL1 genes up to doubled the risk of coronary heart disease, while the JAK2 V617F mutation was linked to a much higher — 12 times — risk of coronary heart disease.

TET2, ASXL1, and JAK2 mutations were also enriched among participants with early-onset myocardial infarction in the ATVB and PROMIS cohorts.

Jaiswal and his colleagues suspected that this link between CHIP and coronary heart disease could be driven by increased atherosclerosis. In the BioImage study, they noted that even without coronary heart disease, CHIP carriers had a median coronary artery calcification score that was 3.3 times higher than that of non-carriers.

In a series of mouse model studies, the researchers found that knocking out the CHIP-linked gene TET2 led mice to develop larger atherosclerotic lesions than control mice and that macrophages from TET2 knockout mice had elevated levels of cytokines and chemokines that contribute to atherosclerosis formation.

Further, in the PROMIS cohort, the researchers noted that people with TET2 mutations had higher levels of the circulating chemokine interleukin-8 than those without such variants.

This suggested to Jaiswal and his colleagues that somatic mutations contribute to the development of atherosclerosis.

"Beyond the mutations that you inherit from your parents, this work reveals a new genetic mechanism for atherosclerosis — mutations in blood stem cells that arise with aging," said co-senior author Sekar Kathiresan, director of the Broad's Cardiovascular Disease Initiative and an associate professor of medicine at Harvard Medical School.

He and his colleagues added that clonal hematopoiesis could be a modifiable risk factor and targetable by therapeutics.