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Clonal hematopoiesis of indeterminate potential increases CHD risk
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Patients who have clonal hematopoiesis of indeterminate potential in peripheral blood cells had an elevated risk for CHD, according to a study published in The New England Journal of Medicine.
“We found that people acquire mutations in their blood cells as they age, a process called clonal hematopoiesis of indeterminate potential, and those who carry clonal mutations are at markedly increased risk for [MI],” Sekar Kathiresan, MD, co-director of the program in medical and population genetics at the Broad Institute in Cambridge, Massachusetts, associate professor of medicine at Harvard Medical School and director of the Center for Genomic Medicine at Massachusetts General Hospital, said in an interview with Cardiology Today. “The reason for the increased [MI] seems to be enhanced inflammation.”
Siddhartha Jaiswal, MD, PhD, of the division of hematology in the department of medicine at Brigham and Women’s Hospital, and colleagues analyzed data from whole-exome sequencing in participants from four case-control studies, including 4,726 people with CHD and 3,529 controls. Two of the studies were modified nested case-control studies with older participants who were at high CV risk and had long-term follow-up information. The other two studies were retrospective case-control studies with participants who had early-onset MI.
Mutations linked to increased risk
Meta-analysis of both cohorts confirmed that participants who carried clonal hematopoiesis of indeterminate potential had a 1.9 times higher risk for incident CHD vs. noncarriers (95% CI, 1.4-2.7). A combined fixed-effects meta-analysis also showed that clonal hematopoiesis of indeterminate potential was linked to an increased risk for early-onset MI (OR = 4; 95% CI, 2.4-6.7).
Participants with mutations in ASXL1, TET2 and DNMT3A genes had a 1.7 to 2 times increased risk for incident CHD vs. those with no mutations. A mutation of JAK2 V617F was linked to a 12.1 times greater risk for incident CHD than those without the mutation (95% CI, 3.8-38.4).
Those with clonal hematopoiesis of indeterminate potential who did not have incident CHD had a 3.3 times higher median coronary artery calcification score than participants who were noncarriers. Among those with incident CHD, the median CAC score in participants who were carriers was 1.8 times higher vs. noncarriers.
Effects of Tet2 mutations
Researchers also reviewed data from atherosclerosis-prone mice who were implanted with bone marrow from Tet2 control mice or homozygous or heterozygous knockout mice. At 5 weeks, the median lesion size in the aortic root in mice that received bone marrow from Tet2 knockout mice was two times larger than mice that received control bone marrow (P = .02). The increase persisted at 9 weeks (1.7 times; P = .01), 13 weeks (1.4 times; P = .03) and 17 weeks (2.7 times; P = .02).
Chemokines or cytokines were found in an upregulated class of genes in Tet2 knockout macrophages, based on a gene set enrichment analysis.
“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 when aging,” Kathiresan told Cardiology Today.
“Important questions remain,” John F. Keaney Jr., MD, professor at the University of Massachusetts Medical School in Worcester, wrote in a related editorial. “We do not know whether all the somatic mutations associated with [clonal hematopoiesis of indeterminate potential] work by the same mechanism as TET2, so we cannot yet determine whether inflammation is the best therapeutic target for these patients. In addition, we do not know whether [clonal hematopoiesis of indeterminate potential] or specific mutations in [clonal hematopoiesis of indeterminate potential] driver genes have an effect on other traditional risk factors for [CVD] in a way that might also promote atherosclerosis.” – by Darlene Dobkowski
Disclosures: Jaiswal reports a patent relating to a method to identify and treat a patient with a predisposition to or afflicted with a cardiometabolic disease. Kathiresan reports receiving grant support from Bayer, personal fees from Alnylam, AstraZeneca, Bayer, Catabasis, Celera, Corvidia Therapeutics, Eli Lilly, Genomics plc, Ionis, Leerink Partners, Merck, Noble Insights, Novartis, Regeneron Genetics Center and Sanofi, and other support from Catabasis and San Therapeutics. Please see the full study for a list of the other researchers’ relevant financial disclosures. Keaney reports serving as an associate editor at The New England Journal of Medicine.
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