Sex Chromosome Loss and Clonal Hematopoesis in Thoracic Aortic Disease

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Somatic mosaicism is emerging biomarker of cardiometabolic disease and increased mortality. Loss of one sex chromosome (SCL), causing mosaicism for a 45,X cell line, and clonal hematopoesis (CH) of hyperproliferative stem cells with a founder genetic mutation, are dramatically increased in peripheral blood samples of patients with heart failure and atherosclerotic vascular disease. The association between CH or SCL and thoracic aortic aneurysms or acute aortic dissections (TAD) has not been determined, but both genetic changes are mechanistically linked to TAD. Constitutional absence of the second sex chromosome is associated with a 50-fold increased risk for TAD in people with Turner syndrome. Myeloid clones with CH mutations secrete inflammatory cytokines that may accelerate the pathogenesis of TAD and contribute to dissections. We hypothesize that CH and SCL are enriched in TAD and are correlated with aortic pathology and the likelihood of subsequent aortic events. Specific Aim 1: Determine the prevalence and enrichment of CH and SCL in TAD We will identify CH and SCL in 200 whole exome sequences from the GenTAC BioLINCC repository, using validated methods to call mosaic sequence variants. All subjects who were less than 55 years old when TAD was diagnosed are eligible for inclusion. The prevalence of CH and SCL will be compared to control samples from age and sex-matched individuals without any history of aortic disease. We will replicate our findings using data and samples from local TAD cohorts. Specific Aim 2. Determine the association between CH and SCL and clinical outcomes Using registry data, we will compare the clinical characteristics of CH and SCL carriers and non-carriers, including genetic diagnosis, age at presentation, sex, aortic valvular disease, and clinical outcomes including aortic dissection, aortic surgery or death. CH and SCL have emerged as common and powerful drivers of cardiovascular disease and death. The overall goal of this proposal is to determine the association between CH and SCL and the incidence and outcomes of TAD. Our findings have the potential to identify a new class of genetic modifiers, biomarkers and potential therapies for thoracic aortic disease.