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      Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d8552255e272">Background</h5> <p id="P1">Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of an expanded somatic blood cell clone in those without other hematologic abnormalities, is common in older individuals and associates with an increased risk of developing hematologic cancer. We previously found preliminary evidence for an association of CHIP with human atherosclerotic cardiovascular disease, but the nature of this association was unclear. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d8552255e277">Methods</h5> <p id="P2">We used whole exome sequencing to detect the presence of CHIP in peripheral blood cells and associated this with coronary heart disease in four case-control studies together comprising 4,794 cases and 3,537 controls. To assess causality, we perturbed the function of <i>Tet2,</i> the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d8552255e285">Results</h5> <p id="P3">In nested case-control analyses from two prospective cohorts, carriers of CHIP had a 1.9-fold (95% confidence interval 1.4–2.7) increased risk of coronary heart disease compared to non-carriers. In two retrospective case-control cohorts for early-onset myocardial infarction, those with CHIP had a 4.0-fold greater risk (95% confidence interval 2.4–6.7) of having myocardial infarction. Mutations in <i>DNMT3A, TET2, ASXL1,</i> and <i>JAK2</i> were each individually associated with coronary heart disease. Those with clonal hematopoiesis also had increased coronary artery calcification, a marker of coronary atherosclerosis burden. Hyperlipidemic mice engrafted with <i>Tet2−/−</i> or <i>Tet2+/−</i> bone marrow developed larger atherosclerotic lesions in the aortic root and aorta than mice receiving control marrow. Analyses of <i>Tet2−/−</i> macrophages demonstrated elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d8552255e305">Conclusions</h5> <p id="P4">Clonal hematopoiesis robustly associates with coronary heart disease in humans and causes accelerated atherosclerosis in mice. </p> </div>

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          Most cited references15

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          The Framingham Offspring Study. Design and preliminary data.

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            Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia.

            Given that most bone marrow cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing hematopoietic stem cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions.
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              Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice.

              Since the first example of conditional gene targeting in mice in 1994, the use of Cre recombinase and loxP flanked sequences has become an invaluable technique to generate tissue and temporal specific gene knockouts. The number of mouse strains expressing floxed-gene sequences, and tissue-specific or temporal-specific Cre-recombinase that have been reported in the literature has grown exponentially. However, increased use of this technology has highlighted several problems that can impact the interpretation of any phenotype observed in these mouse models. In particular, accurate knowledge of the specificity of Cre expression in each strain is critical in order to make conclusions about the role of specific cell types in the phenotypes observed. Cre-mediated deletion specificity and efficiency have been described in many different ways in the literature, making direct comparisons between these Cre strains impossible. Here we report crossing thirteen different myeloid-Cre mouse strains to ROSA-EYFP reporter mice and assaying YFP expression in a variety of naïve unstimulated hematopoietic cells, in parallel. By focusing on myeloid subsets, we directly compare the relative efficiency and specificity of myeloid deletion in these strains under steady-state conditions.
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                New England Journal of Medicine (NEJM/MMS)
                0028-4793
                1533-4406
                July 13 2017
                July 13 2017
                : 377
                : 2
                : 111-121
                Article
                10.1056/NEJMoa1701719
                6717509
                28636844
                8577918d-7aed-4f25-a161-d9333d90612a
                © 2017
                History

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