Sex Chromosome Loss and Clonal Hematopoesis in Thoracic Aortic Disease

胸主动脉疾病中的性染色体丢失和克隆造血

• 批准号: 10021024
• 负责人: SIDDHARTH KUMAR PRAKASH
• 金额: $ 11.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021024
• 关键词: Acute; Age; Aortic Aneurysm; Aortic Diseases; Atherosclerosis; Biological Markers; Blood specimen; Cardiovascular Diseases; Cell Line; Cessation of life; Characteristics; Chest; Clinical; Constitutional; DNA Sequence Alteration; Data; Diagnosis; Diagnostic tests; Disease; Dissection; Event; Genetic; Goals; Heart failure; Incidence; Individual; Inflammatory; Life; Link; Methods; Mosaicism; Mutation; Myelogenous; Myeloid Cells; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Patients; Penetrance; Prevalence; Recording of previous events; Risk; Risk Factors; Sampling; Severities; Sex Chromosomes; Sudden Death; Thoracic Aortic Aneurysm; Turner' s Syndrome; Variant; age related; aortic valve disorder; cardiometabolism; chromosome loss; cohort; cytokine; data registry; exome; follow-up; genetic disorder diagnosis; mortality; novel diagnostics; peripheral blood; prevent; repository; sex; stem cells; vascular inflammation

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.

体细胞镶嵌是心脏代谢疾病的新兴生物标志物，死亡率增加。 一个性别染色体（SCL）的丧失，导致45，X细胞系和克隆血小化的镶嵌性 （CH）具有创始人基因突变的高增殖性干细胞，在 心力衰竭和动脉粥样硬化血管疾病患者的外周血样本。这 CH或SCL与胸部主动脉瘤或急性主动脉夹层（TAD）之间的关联 没有确定，但两种遗传变化在机械上都与TAD相关。宪法 缺乏第二性染色体与人们的TAD风险增加50倍 与特纳综合症有关。 CH突变的髓样克隆分泌炎症细胞因子可能 加速TAD的发病机理并有助于解剖。我们假设CH和SCL 富含TAD，与主动脉病理学和随后主动脉的可能性相关 事件。 特定目的1：确定TAD中CH和SCL的患病率和富集，我们将 使用Gentac Biolincc存储库中的200个整个外显子组序列中的CH和SCL，使用 经过验证的方法调用镶嵌序列变体。所有不到55岁的受试者 诊断出TAD时，有资格纳入。将比较CH和SCL的患病率 从年龄和性别匹配的个体中控制样本，而没有任何主动脉疾病史。我们将 使用来自本地TAD队列的数据和样本来复制我们的发现。 具体目标2。使用CH和SCL之间的关联以及使用临床结果 注册表数据，我们将比较CH和SCL载体和非载体的临床特征， 包括遗传诊断，表现年龄，性别，主动脉瓣膜疾病和临床结果 包括主动脉夹层，主动脉手术或死亡。 CH和SCL已成为心血管疾病的常见和强大驱动因素， 死亡。该提案的总体目标是确定CH和SCL与SCL之间的关联 TAD的发生率和结果。我们的发现有可能识别一类新的遗传 修饰剂，生物标志物和胸腔主动脉疾病的潜在疗法。