Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

作者：Siddhartha Jaiswal, Pradeep Natarajan, Alexander J. Silver, Christopher J. Gibson, Alexander G. Bick, Eugenia Shvartz, Marie McConkey, Namrata Gupta, Stacey Gabriel, Diego Ardissino, Usman Baber, Roxana Mehran, Valentı́n Fuster, John Danesh, Philippe Frossard, Danish Saleheen, Olle Melander, Galina K. Sukhova, Donna Neuberg, Peter Libby, Sekar Kathiresan, Benjamin L. Ebert · 发表于：New England Journal of Medicine · 年份：2017 · DOI：10.1056/nejmoa1701719 · 被引用次数：2708 · 研究领域：Acute Myeloid Leukemia Research、Myeloproliferative Neoplasms: Diagnosis and Treatment、Blood disorders and treatments

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. METHODS: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. RESULTS: In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutat...