Somatic mutations reveal clonal cell populations in atherosclerotic plaques

Abstract

ABSTRACTIn recent years, the potential involvement of clonal cell populations in atherosclerosis has emerged.Evidence from independent research groups unambiguously showed that smooth muscle cells clonally expand in experimental atherosclerosis, and clonal hematopoiesis of indeterminate potential (CHIP) was identified as a novel independent risk factor for atherosclerotic cardiovascular disease. However, whether clonal cell populations contribute to human atherosclerotic lesions remains elusive.In this study, we performed deep whole-exome sequencing of 32 segments from 14 carotid plaques of patients undergoing carotid endatherectomy. We unveiled a landscape of somatic mutations confined to plaque tissue (i.e., not detected in patient-matched buffy coats). Based on variant allele frequencies, we estimated that individual locally expanded clones contributed with up to 15% of plaque segment cell content. In addition, seven patients were CHIP carriers and in several of these patients, hematopoietic clones comprised over 30% of the cell population of plaque segments.Taken together, we provide evidence that somatic mutations and clonal cell populations (expanded locally or invading from the circulation) are inherent features of atherosclerosis.