Aortic aneurysms and dissections are the major diseases affecting the aorta, and a leading cause of morbidity and mortality in the United States. Thoracic aortic aneurysms progressively enlarge over time, leading to life-threatening type A dissections (TAAD) in the absence of prophylactic surgical repair. TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance in up to 19% of TAAD patients. We mapped the first locus for the condition, the TAAD1 locus at 5q13-14, which is responsible for approximately 10-30% of familial disease, and proceeded to map a second locus for TAAD, the TAAD2 locus at 3p24-25, responsible for approximately 5% of familial disease. Clinical studies have delineated differences in the phenotype in families linked to TAAD1 versus TAAD2. Recently, we have determined that the defective gene at the TAAD2 locus encodes the transforming growth factor p receptor type II, suggesting that dysregulation of the TGFp pathway may be a mechanism leading to aneurysms. In 30% of our TAAD families, linkage of the phenotype to markers at known loci is excluded, providing evidence that one or more loci for the disease are yet to be identified. We hypothesize that there are multiple genes responsible for familial TAAD, and differences in the phenotype will distinguish families with disease due to mutations in the various genes. The long-term goal of the proposed project is to identify the genes that cause familial TAAD and characterize, the associated phenotype.
The first aim i s to identify, characterize and collect samples from TAAD families. We have identified 278 families with 2 or more members with TAAD, and we propose to continue to recruit families with a focus on large families with multiple living, affected members.
Aim 2 will map a third locus for familial TAAD (TAAD3) using samples from a single family with multiple affected members. We have identified a four generation family in whom the phenotype is not linked to known loci that will be used to map this novel locus.
Aim 3 proposes to use the following two stage mapping strategy to identify another major locus responsible for 20-30% of familial TAAD: (1) affected relative pair (ARP) linkage analysis using 2 samples from affected individuals from 100 unrelated TAAD families; (2) fine mapping using the entire cohort.
The final aim i s to refine and narrow the critical interval at the TAAD1 locus using a shared SNP haplotype mapping strategy and identify the defective gene within the critical region. Through these specific aims, we will map novel loci for TAAD and identify further gene(s) causing the disease. If thoracic aortic aneurysms are diagnosed, followed medically, and surgically repaired prior to dissection, the life expectancy of the affected individual is significantly improved. Therefore, identification of the genes that predispose individuals to TAAD is critical in preventing premature deaths due to dissections.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062594-07
Application #
7326808
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Goldberg, Suzanne H
Project Start
2001-12-18
Project End
2009-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
7
Fiscal Year
2008
Total Cost
$379,885
Indirect Cost
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
Prakash, Siddharth K; Milewicz, Dianna M (2018) X Marks the Spot: The Profound Impact of Sex on Aortic Disease. Arterioscler Thromb Vasc Biol 38:9-11
Regalado, Ellen S; Mellor-Crummey, Lauren; De Backer, Julie et al. (2018) Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations. Genet Med 20:1206-1215
Guo, Dong-Chuan; Regalado, Ellen S; Pinard, Amelie et al. (2018) LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections. Am J Hum Genet 102:706-712
Guo, Dong-Chuan; Hostetler, Ellen M; Fan, Yuxin et al. (2017) Heritable Thoracic Aortic Disease Genes in Sporadic Aortic Dissection. J Am Coll Cardiol 70:2728-2730
Milewicz, Dianna M; Trybus, Kathleen M; Guo, Dong-Chuan et al. (2017) Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections. Arterioscler Thromb Vasc Biol 37:26-34
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Milewicz, Dianna; Hostetler, Ellen; Wallace, Stephanie et al. (2016) Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene. J Cardiovasc Surg (Torino) 57:172-7
Jondeau, Guillaume; Ropers, Jacques; Regalado, Ellen et al. (2016) International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 9:548-558
Guo, Dong-chuan; Regalado, Ellen S; Gong, Limin et al. (2016) LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res 118:928-34
Karimi, Ashkan; Milewicz, Dianna M (2016) Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure. Can J Cardiol 32:26-34

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