Heart disease risk: Aging, mutation, blood cells...oh my!

New research on age-related blood cell mutations and risk for cardiovascular disease points to inflammation as a key player in heart disease

Jeffrey Bouley
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CAMBRIDGE, Mass.—Scientists at the Broad Institute of MIT and Harvard have found that a set of genetic mutations in blood cells that arises during aging may be a major new risk factor for cardiovascular disease. The Broad Institute researchers point out that this contrasts significantly with inherited genetic predispositions and traditional lifestyle risk factors, such as smoking or an unhealthy diet; these recently researched mutations are “somatic mutations” of stem cells in bone marrow that originate in those cells as people age.
 
Such mutations aren’t uncommon—more than 10 percent of people aged 70 or older have at least one of them. Given their frequency, they could represent a good target for screening (in terms of potential future screening methods) so that risk of cardiovascular disease can be reduced through lifestyle changes or therapeutic interventions, according to the Broad Institute.
 
“There is more work to be done, but these results demonstrate that pre-malignant mutations in blood cells are a major cause of cardiovascular disease that in the future may be treatable either with standard therapies or new therapeutic strategies based on these findings,” said Benjamin Ebert, a co-senior author of the new study, an institute member at the Broad, a professor of medicine at Harvard Medical School and a hematologist at Brigham and Women’s Hospital.
 
The work was featured in the New England Journal of Medicine in June under the title “Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.”
 
Admittedly, this area of research is ground that has been trod before in various ways. Nature Medicine in 2014 published “Age-related mutations associated with clonal hematopoietic expansion and malignancies” from St. Louis-based researchers at Washington University, and Boston University Medical College researchers shared research earlier this year looking into the notion that aging is associated with an increase in somatic mutations in the hematopoietic system and that this might have a direct relationship on the development of atherosclerosis.
 
However, while it may not be an entirely novel area of study, the work by the Broad researchers contributes to the broader understanding of pathogenesis in coronary heart disease by supporting the hypothesis that inflammation, in addition to elevated cholesterol levels, plays an important role in this disease area and potentially other diseases of aging.
 
“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,” explained first author Siddhartha Jaiswal, a pathologist at Massachusetts General Hospital and researcher in the Ebert lab. “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.”
 
Previous research led by Ebert and Jaiswal revealed that some somatic mutations that are able to confer a selective advantage to blood stem cells become much more frequent with aging. They named this condition “clonal hematopoiesis of indeterminate potential” (CHIP) and found that it increases the risk of developing a blood cancer more than tenfold—it also seems to increase mortality from heart attacks or stroke.
 
In the new Broad study, data from four case-control studies on more than 8,000 people were analyzed, with the finding that possessing just one of the CHIP-related mutations nearly doubled the risk for coronary heart disease. The mutations conferred an even greater risk in people who have previously had a heart attack before age 50.
 
While the human genetics data showed a strong association between CHIP and coronary heart disease, the team hoped to uncover the underlying biology, notes the Broad Institute. Using a mouse model prone to developing atherosclerosis, the scientists showed that loss of one of the CHIP-mutated genes, Tet2, in bone marrow cells leads to larger atherosclerotic plaques in blood vessels, evidence that this mutation can accelerate atherosclerosis in mice.
 
Atherosclerosis is commonly believed to be a disease of chronic inflammation that can arise in response to excess cholesterol in the vessel wall, the Broad explains, and to examine this on a cellular level, the team turned to the macrophage, an immune cell found in atherosclerotic plaques that can develop from CHIP stem cells and carry the same mutations. Because Tet2 and other CHIP-related mutations are known to be so-called “epigenetic regulators” that can alter the activity of other genes, the team examined gene expression levels in the Tet2-mutated macrophages from mice. Such mutated cells appear to be “hyper-inflammatory” with increased expression of inflammatory molecules that contribute to atherosclerosis, according to the team’s findings.
 
Furthermore, humans with Tet2 mutations also had higher levels of one of these molecules, IL-8, in their blood. Boiling down the chain of relationships to the basics, CHIP is associated with coronary heart disease in humans, mutation of the CHIP-related gene Tet2 causes atherosclerosis in mice and an inflammatory mechanism is quite likely to be a foundational element of this process.
 
But again, that is a simplified view of the complexities that are involved in any disease, cardiovascular diseases among them, and thus the researchers stress that more work is needed to show whether other genes that are mutated in CHIP also lead to increased inflammation. The team is also exploring whether interventions such as cholesterol lowering therapy or anti-inflammatory drugs might have benefit in people with CHIP.
 
Because inflammation is quite likely to modulate several other diseases related to aging, like autoimmune disorders and neurodegenerative disease—and because CHIP frequency increase with aging—somatic mutations might lie at the heart of any number of age-related diseases.
 
“By combining genetic analysis on large cohorts with disease model and gene expression studies, we’ve been able to confirm the earlier hints of CHIP’s surprising role in cardiovascular disease,” said co-senior author Sekar Kathiresan, director of the Broad’s Cardiovascular Disease Initiative, associate professor of medicine at Harvard Medical School, and director of the Center for Genomic Medicine at Massachusetts General Hospital. “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.”

Jeffrey Bouley

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