Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

描述（由申请人提供）：胸主动脉瘤和夹层是影响胸主动脉的主要疾病，也是美国发病率和死亡率的常见原因。胸主动脉瘤随着时间的推移逐渐扩大，最终导致急性主动脉夹层（TAAD）;如果在夹层之前手术修复动脉瘤，可以预防过早死亡。TAAD以常染色体显性方式遗传，在高达20%的TAAD患者中具有可变表达和降低的遗传率（家族性TAAD）。我们已经绘制了FTAAD的五个染色体位点，并确定了五个基因，当突变引起FTAAD，FBN 1，TGFBR 2，TGFBR 1，ACTA 2和MYLK;其他研究人员已经确定MYH 11作为第六个基因。最近，基于家族的外显子组测序确定SMAD 3突变为引起FTAAD的第七个基因。总的来说，这些基因的突变导致了大约20%的FTAAD。这些基因的鉴定提供了对该疾病发病机制的深入了解，突出了异常的转化生长因子-β信号传导和破坏平滑肌收缩作为TAAD的促成因素。特定基因突变与相应表型之间的相关性揭示了与每个基因相关的独特特征，从而建议FTAAD家族中的疾病管理应基于特定的遗传缺陷。我们假设有多个基因负责家族性TAAD，这种遗传异质性是FTAAD中观察到的显著临床异质性的基础。该项目的长期目标是确定导致FTAAD的基因并表征相关表型。第一个目的是招募有两个或两个以上TAAD成员的家庭，收集样本，并描述这些家庭的临床表型。第二个目标是使用具有多个受影响成员的大家族来绘制FTAAD的染色体位点。第三个目标是通过对来自大家族的受影响的亲属对进行外显子组测序来识别新的FTAAD基因，并将这些数据与连锁数据相结合，以有效地识别致病基因中的罕见变异。最后，将进行初步的病理学、细胞学和分子学研究，以便开始了解基因突变对主动脉功能的影响。通过这些研究，我们将提高对主动脉疾病病因的认识，并为家族性胸主动脉疾病的正确临床治疗提供关键数据。 公共卫生相关性：在美国，急性主动脉夹层是过早死亡的常见原因，排名高达第15位。拟议研究的目标是通过识别遗传上易患该疾病的个体并启动药物和手术治疗以预防夹层，从而预防因主动脉夹层导致的过早死亡。

DESCRIPTION (provided by applicant): Thoracic aortic aneurysms and dissections are the major diseases affecting the thoracic aorta and a common cause of morbidity and mortality in the United States. Thoracic aortic aneurysms progressively enlarge over time and ultimately lead to acute aortic dissections (TAAD); if the aneurysm is surgically repaired prior to dissection premature deaths can be prevented. TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance in up to 20% of TAAD patients (Familial TAAD). We have mapped five chromosomal loci for FTAAD and identified five genes that when mutated cause FTAAD, FBN1, TGFBR2, TGFBR1, ACTA2, and MYLK; other investigators have identified MYH11 as a sixth gene. Recently, family-based exome sequencing identified mutations in SMAD3 as the seventh gene causing FTAAD. In total, mutations in these genes are responsible for approximately 20% of FTAAD. Identification of these genes has provided insight into the pathogenesis of the disease, highlighting aberrant transforming growth factor-¿ signaling and disrupted smooth muscle contraction as factors contributing to TAAD. Correlation between mutations in specific genes and the corresponding phenotype has revealed unique features associated with each gene, leading to recommendation that disease management in FTAAD families be based on the specific genetic defect. We hypothesize that there are multiple genes responsible for familial TAAD, and this genetic heterogeneity underlies the significant clinical heterogeneity observed in FTAAD. The long term goal of the project is to identify the genes that cause FTAAD and characterize the associated phenotype. The first aim is to recruit families with two or more members with TAAD, collect samples, and characterize the clinical phenotype of these families. The second aim is to map chromosomal loci for FTAAD using large families with multiple affected members. The third aim is to identify novel FTAAD genes through exome sequencing of affected relative pairs from large families and combining these data with the linkage data to efficiently identify rare variants in disease-causing genes. Finally, initial pathologic, cellular, and molecular studies will be done to begin to understand the effect of gene mutations on aortic function. Through these studies, we will improve understanding of the etiology of aortic diseases and provide data critical for the proper clinical management of familia thoracic aortic disease. PUBLIC HEALTH RELEVANCE: Acute aortic dissections are a common cause of premature death in the United States, ranking as high as the 15th leading cause of death. The goal of the proposed research is to prevent premature deaths due to aortic dissections by identifying individuals who are genetically predisposed to the disease and initiating medical and surgical therapies to prevent dissections.