Genetic Determinants of Thoracic Aortic Aneurysms and Dissection

胸主动脉瘤和夹层的遗传决定因素

• 批准号: 7140871
• 负责人: Xing-Li Wang
• 金额: $ 46.84万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140871
• 关键词: aorta aneurysm; bioinformatics; cardiovascular function; collagen; elastin; extracellular matrix; gene environment interaction; gene expression profiling; gene interaction; genetic susceptibility; histopathology; human genetic material tag; human tissue; hypertension; inflammation; pathologic process; patient oriented research; population genetics; single nucleotide polymorphism; smoking; statistics /biometry; tobacco abuse; vascular smooth muscle

Thoracic aortic aneurysm and/or dissection (TAA/TAD) is the 16th cause of death in USA. It differs from the other common form of aneurysm - abdominal aortic aneurysm (AAA) both clinically and pathologically. Little data, however, are available specifically for the pathogenesis of TAA/TAD. We hypothesize that genetic variants contribute significantly to the sporadic TAA and TAD. This genetically determined susceptibility is modifiable or conditional on the presence of other factors including cigarette smoking, hypertension and inflammation, which directly interact with aortic wall integrity and remodeling. We will employ a targeted candidate gene approach and determine representatively distributed single nucleotide polymorphisms (SNPs) in 800 chronic TAA patients, 400 chronic co-existing TAA and TAD patients, 200 acute TAD patients and 800 healthy controls of age- gender- matched to TAA patients. We will measure selected 1500 SNPs from 138 genes (approximately 10 SNPs/gene) with their products regulating arterial wall ECM equilibrium. Specifically, we will (1) determine genetic variants that may be associated with the clinical endpoints of the development and progression of thoracic aortic aneurysm (TAA) and dissection (TAD); (2) investigate the genetic variants that may be associated with histopathological endpoints in aortic wall; (3) fine-mapping and re-sequencing the candidate genes in which SNPs have been found to be associated with clinical diseases or pathological phenotypes. We will determine expression profiles of these candidate genes and related to genotypes of the significant SNPs as the first step in defiining functional SNPs. Using maximum likelihood based statistical models, we will identify genes and their variants that are associated with clinical diagnosis of TAA/TAD, pathological changes in aortic wall and biochemical intermediate phenotypic traits. This project will document risk factors predicting TAA/TAD, genes and their variants predisposing TAA/TAD, genotype-environmental specific susceptibility to TAA/TAD development and progression. Our study is novel in exploring the genetic associations with three unique phenotypic endpoints: clinical, histopathological and biochemical. Our project is feasible since we will use a welldeveloped population genetic model to investigate the novel hypothesis. Our study will lead to discoveries that can be potentially used clinically for diagnosis, prognosis and guidance for treatment strategies.

胸部主动脉瘤和/或解剖（TAA/TAD）是美国死亡的第16个原因。它 临床和 病理性。但是，很少有数据专门用于TAA/TAD的发病机理。我们 假设遗传变异对零星的TAA和TAD有显着贡献。从遗传上讲 确定的易感性是可修改的或有条件的，以其他因素在内 吸烟，高血压和炎症，它们直接与主动脉壁完整性和重塑相互作用。我们 将采用靶向候选基因方法并确定代表性分布的单核苷酸 800名慢性TAA患者的多态性（SNP），400例慢性共存的TAA和TAD患者，200 与TAA患者相匹配的年龄性别的急性TAD患者和800例健康对照。我们将衡量 从138个基因（约10个SNP/基因）中选择了1500个SNP，其产品调节动脉壁ECM 平衡。具体而言，我们将（1）确定可能与临床有关的遗传变异 胸部主动脉瘤（TAA）和解剖（TAD）发育和进展的终点； （2） 研究可能与主动脉壁中组织病理学终点相关的遗传变异。 （3） 精细映射并重新列出已发现SNP与之相关的候选基因 临床疾病或病理表型。我们将确定这些候选者的表达概况 基因和与显着SNP的基因型有关，作为偏转功能性SNP的第一步。使用 基于最大似然的统计模型，我们将识别相关的基因及其变体 通过对TAA/TAD的临床诊断，主动脉壁和生化中间体的病理变化 表型特征。该项目将记录预测TAA/TAD，基因及其变体的风险因素 诱发taa/tad，基因型 - 环境特定的特异性敏感性和TAA/TAD发育和 进展。我们的研究在探索与三种独特表型的遗传关联方面是新颖的 终点：临床，组织病理学和生化。我们的项目是可行的，因为我们将使用一个开发的 人群遗传模型研究了新假设。我们的研究将导致发现 可以在临床上用于诊断，预后和治疗策略指导。