Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

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>