Thoracic aortic aneurysm and/or dissection (TAA/TAD) is the 16th cause of death in USA. Itdiffers from the other common form of aneurysm - abdominal aortic aneurysm (AAA) both clinically andpathologically. Little data, however, are available specifically for the pathogenesis of TAA/TAD. Wehypothesize that genetic variants contribute significantly to the sporadic TAA and TAD. This geneticallydetermined susceptibility is modifiable or conditional on the presence of other factors including cigarettesmoking, hypertension and inflammation, which directly interact with aortic wall integrity and remodeling. Wewill employ a targeted candidate gene approach and determine representatively distributed single nucleotidepolymorphisms (SNPs) in 800 chronic TAA patients, 400 chronic co-existing TAA and TAD patients, 200acute TAD patients and 800 healthy controls of age- gender- matched to TAA patients. We will measureselected 1500 SNPs from 138 genes (approximately 10 SNPs/gene) with their products regulating arterial wall ECMequilibrium. Specifically, we will (1) determine genetic variants that may be associated with the clinicalendpoints 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 withclinical diseases or pathological phenotypes. We will determine expression profiles of these candidategenes and related to genotypes of the significant SNPs as the first step in defiining functional SNPs. Usingmaximum likelihood based statistical models, we will identify genes and their variants that are associatedwith clinical diagnosis of TAA/TAD, pathological changes in aortic wall and biochemical intermediatephenotypic traits. This project will document risk factors predicting TAA/TAD, genes and their variantspredisposing TAA/TAD, genotype-environmental specific susceptibility to TAA/TAD development andprogression. Our study is novel in exploring the genetic associations with three unique phenotypicendpoints: clinical, histopathological and biochemical. Our project is feasible since we will use a welldevelopedpopulation genetic model to investigate the novel hypothesis. Our study will lead to discoveriesthat can be potentially used clinically for diagnosis, prognosis and guidance for treatment strategies.
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