Genetic Determinants of Thoracic Aortic Aneurysms and Dissection

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

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