Sex Chromosome Loss and Clonal Hematopoesis in Thoracic Aortic Disease

体细胞嵌合现象是心脏代谢疾病和死亡率增加的新兴生物标志物。 一条性染色体（SCL）丢失，导致45，X细胞系嵌合体和克隆造血 (CH)具有创始人基因突变的过度增殖干细胞，在 心力衰竭和动脉粥样硬化性血管疾病患者的外周血样品。的 CH或SCL与胸主动脉瘤或急性主动脉夹层之间的相关性， 尚未确定，但这两种遗传变化都是机械地与糖尿病有关。宪法 缺乏第二性染色体的人患乳腺癌的风险增加50倍 特纳综合症具有CH突变的髓系克隆分泌炎性细胞因子， 加速胰腺炎的发病并促进夹层。我们假设CH和SCL 富含维生素C，与主动脉病变和随后的主动脉粥样硬化的可能性相关。 事件 具体目标1：确定CH和SCL的患病率和富集度， 在GenTAC BioLINCC库的200个全外显子组序列中鉴定CH和SCL，使用 验证的方法来调用镶嵌序列变体。所有年龄小于55岁的受试者 当被诊断出患有糖尿病时，有资格入选。比较CH和SCL的患病率 对照样本来自年龄和性别匹配的无任何主动脉疾病史的个体。我们将 使用当地研究群体的数据和样本复制我们的发现。 具体目标2。确定CH和SCL与临床结局之间的关系， 登记数据，我们将比较CH和SCL携带者和非携带者的临床特征， 包括基因诊断、发病年龄、性别、主动脉瓣疾病和临床结果 包括主动脉夹层主动脉手术或死亡 CH和SCL已经成为心血管疾病的常见和强大的驱动因素， 死亡本建议的整体目标是确定CH和SCL之间的关联， 的发生率和结局。我们的发现有可能识别出一类新的遗传 调节剂、生物标志物和潜在的治疗方法。

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.