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Clonal hematopoiesis of indeterminate potential and cardiovascular disease

Published:September 02, 2022DOI:https://doi.org/10.1016/j.trsl.2022.08.013

      ABSTRACT

      Age is the most important risk factor for cardiovascular disease and appears to be more than a marker of cumulative exposure to other risk factors such as dyslipidemia and hypertension. With aging, genetic mutations occur that are not present in our germline DNA, observed as somatic mosaicism. Hematopoietic stem cells have an increased chance of developing mosaicism because they are highly proliferative, and mutations with survival benefits can establish clonal populations. Age-related clonal hematopoiesis resulting from somatic mutations was first described ∼25 years ago. The subset of clonal hematopoiesis in which a driver mutation with variant allele frequency of at least 2% occurs in a gene implicated in hematologic malignancies but in the absence of known hematologic malignancy or other clonal disorder is termed clonal hematopoiesis of indeterminate potential (CHIP). Large-scale exome-sequencing projects have recently enabled the study of CHIP frequency, gene-specific analyses, and longitudinal clinical consequences of CHIP, including an observed increased risk for cardiovascular disease. Animal models provide insight into the mechanisms by which CHIP increases cardiovascular disease risk, and combined animal, clinical, and epidemiological data suggest therapeutic implications for CHIP in cardiovascular disease prevention.

      Abbreviations:

      AIM2 (absent in melanoma–2), ASCVD (atherosclerotic cardiovascular disease), BM (bone marrow), CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), CHD (coronary heart disease), CHIP (clonal hematopoiesis of indeterminate potential), CI (confidence interval), FUSION (Finland–United States Investigation of NIDDM Genetics), HR (hazard ratio), HSC (hematopoietic stem cell), IL (interleukin), LDL (low-density lipoprotein), MGBB (Mass General Brigham Biobank), NLRP3 (nucleotide-binding oligomerization domain–like receptor family pyrin domain containing–3), OR (odds ratio), PAD (peripheral artery disease), UKBB (UK Biobank), VAF (variant allele frequency. Non-peer-reviewed references are indicated as #P, preprint and #A, abstract)
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