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 i s to recruit families with two or more members with TAAD, collect samples, and characterize the clinical phenotype of these families.
The second aim i s to map chromosomal loci for FTAAD using large families with multiple affected members.
The third aim i s 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL109942-01A1
Application #
8297854
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Tolunay, Eser
Project Start
2012-04-12
Project End
2016-03-31
Budget Start
2012-04-12
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$693,693
Indirect Cost
$218,627
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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Milewicz, Dianna M; Regalado, Ellen S; Shendure, Jay et al. (2014) Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med 24:53-60
Milewicz, Dianna M; Reid, Amy J; Cecchi, Alana C (2014) Vascular Ehlers-Danlos syndrome: exploring the role of inflammation in arterial disease. Circ Cardiovasc Genet 7:5-7