The Hematologist

September-October 2017, Volume 14, Issue 5

CHIP and Coronary Heart Disease: Clonal Hematopoiesis Increases Atherosclerosis

Andrew Roberts, MBBS, PhD, FRACP, FRCPA Metcalf Chair of Leukaemia Research
University of Melbourne, Melbourne, Australia

Published on: August 14, 2017

Jaiswal S, Natarajan P, Silver AJ, et al. Clonal Hematopoiesis and Risk of Atherosclerosis Cardiovascular Disease. N Engl J Med. 2017;377:111-121.

The term CHIP (clonal hematopoiesis of indeterminate potential)1 entered the hematology lexicon after seminal research from several groups in 2014 revealed that upwards of 10 percent of people older than 70 years with normal blood counts have readily detectable mutations in genes associated with acute myeloid leukaemia and myelodysplasia.2-4 That these people had a 10-fold higher risk of developing hematologic cancer, and an excess mortality seemed logical given accepted models of leukemogenesis. Surprisingly, however, much of the higher risk of death in one study was due to coronary heart disease,2 and this observation required confirmation and further explanation. Dr. Siddhartha Jaiswal and colleagues have now reported a follow-up study that addresses these issues.

Whole-exome sequencing of 74 myeloid cancer associated genes was used to identify CHIP carriers in subjects from multiple large cohort studies established to examine other questions. The association between CHIP and coronary heart disease (CHD) was confirmed using a nested case-control study of subjects enrolled in two prospective cohort studies. An increased risk of experiencing a myocardial infarction or undergoing coronary revascularization was found in each study for CHIP carriers, and meta-analysis calculated that risk to be 1.9 times that of noncarriers. Somatic mutations most commonly occurred in the genes DNMT3A, TET2, and ASXL1, with each carrying a 1.7- to two-fold risk. An association between the degree of coronary artery calcification and the presence of CHIP was found for both those who experienced a CHD event and those who did not, and this was most evident for subjects with a variant allele fraction of 10 percent or greater, corresponding to a clone size of 20 percent or greater. This clone size effect was confirmed in a meta-analysis of four prospective cohort studies: The risk of incident CHD was 2.2 times when the variant allele fraction was 10 percent or more, and 1.4 times when less than 10 percent. A strong association was found for early-onset myocardial infarction (odds ratio, 4.0) in an independent analysis of data from two retrospective case-control studies of CHD in patients younger than 50 years of age. In this younger setting, TET2, JAK2, and ASXL1 showed significant enrichment.

The mechanism by which clonal hematopoiesis contributes to CHD was then investigated experimentally in mice. Irradiated atherosclerosis-prone mice transplanted with Tet2-deficient bone marrow and then fed a high cholesterol diet developed greater aortic atherosclerosis than similarly treated recipients of wild-type bone marrow. The same was true for recipients of Tet2 heterozygous bone marrow — a situation more analogous to CHIP in humans, where TET2 is usually only mutated in one allele. The enhanced atherosclerotic effect occurred without any abnormalities in peripheral blood leukocyte counts being present and without any differences seen compared to controls in fasting serum lipid levels. The investigators hypothesized that Tet2 loss alters the function of macrophages (and their precursor monocytes) in plaques to enhance atherosclerosis. Supportive evidence for this was found in vitro and in vivo using murine models with myeloid-specific Tet2 deficiency. Tet2 loss of function selectively in myeloid cells was sufficient to increase atherosclerosis in the transplant model; LDL induced greater inflammatory signatures and chemokine and cytokine secretion in Tet2-deficient macrophages in vitro; and pro-inflammatory chemokine levels were elevated in vivo in the atherosclerosis transplant model when either Tet2 homozygous or heterozygous mice were compared with wild-type mice as donors. To test the relevance of this observation in the human setting, levels of the chemokine IL-8 were assessed in serum samples from one of the cohort studies. Higher levels of IL-8 were found in TET2-mutant CHIP carriers compared with controls.

Collectively, this report provides strong confirmatory evidence that clonal hematopoiesis with single mutations in either DNMT3A, TET2, ASXL1, or JAK2 is associated with increased risk of CHD, including early onset myocardial infarction, and that the greater the clone size, the higher the risk for both coronary events and atherosclerosis on imaging. A plausible causative mechanism for TET2-mutant CHIP through enhanced pro-inflammatory responses to atherogenic material such as LDL by macrophages arising from the clone is proposed and supported with animal model data. Whether a similar mechanism is relevant for CHIP caused by mutations in DNMT3A, ASXL1, or JAK2, remains to be explored. Nevertheless, for any hematologist seeing a patient with normal blood counts in whom CHIP is suspected based on genetic sequencing performed for personal, research, or medical reasons, it seems important to ensure that their cardiovascular risk factors are being appropriately addressed, as well as excluding the presence of a clinically apparent hematologic malignancy.

References

  1. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9-16.
  2. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-2498.
  3. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477-2487.
  4. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472-1478.

Conflict of Interests

Dr. Roberts indicated no relevant conflicts of interest. back to top