Abdominal aortic aneurysm (AAA) is the dilatation of the abdominal portion of the aorta. The major complication of an untreated AAA is rupture; the risk of fatality from rupture is at least 50%. It is a leading cause of death among the elderly in the U.S.A. The etiology of AAA is unclear. There is strong evidence that AAA aggregates in families, but the causes of familial aggregation are unknown. There are indications that some protein and protease inhibitor loci may be involved in AAA. There is a mouse model for aortic aneurysms. Thus, the evidence favoring a genetic etiology for AAA is strong. There has, however, been little systematic effort to determine the mode of inheritance or to identify genes that are involved in the causation of AAA. The present study aims to investigate the genetic basis of AAA. We propose to collect data on families ascertained through AAA patients. Ultrasound screening of adult asymptomatic relatives of probands will be done to determine their status with respect to AAA. Segregation analysis will be performed to confirm our preliminary evidence of a major recessive gene for AAA susceptibility. To understand the etiology and localize the gene(s) involved in AAA, we shall perform linkage analysis using protein and genomic DNA RFLP markers of members of selected multiplex families. The DNA probes to be used were selected on the basis of recent biochemical and molecular genetic evidence that mutations in the collagen genes, particularly COL3Al, may predispose individuals to develop aortic aneurysms. In addition to the collagen genes, the genes for elastin and for the metallo-proteases collagenase and stromelysin and the serine protease elastase are also considered as candidate genes for AAA susceptibility. Specific tests of genetic heterogeneity will be performed. The possibility that genetic variation at loci known to predispose to cardiovascular disease (apoB, apoE, Lp(a) and the LDL-receptor) contributes to AAA risk will also be investigated. The long-term objectives of this project are to develop methods of genetic analysis of complex diseases. The present project will add to our understanding of the genetic component in the etiology of AAA and improve methods of presymptomatic detection.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Public Health
United States
Zip Code
Helgadottir, Anna; Gretarsdottir, Solveig; Thorleifsson, Gudmar et al. (2012) Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol 60:722-9
Hinterseher, Irene; Erdman, Robert; Donoso, Larry A et al. (2011) Role of complement cascade in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 31:1653-60
Lillvis, John H; Kyo, Yoshiki; Tromp, Gerard et al. (2011) Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19. BMC Med Genet 12:14
Helgadottir, Anna; Thorleifsson, Gudmar; Magnusson, Kristinn P et al. (2008) The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 40:217-24
Peters, D G; Zhang, X-C; Benos, P V et al. (2002) Genomic analysis of immediate/early response to shear stress in human coronary artery endothelial cells. Physiol Genomics 12:25-33
Peters, D G; Kassam, A B; Feingold, E et al. (2001) Molecular anatomy of an intracranial aneurysm: coordinated expression of genes involved in wound healing and tissue remodeling. Stroke 32:1036-42
Vorp, D A; Peters, D G; Webster, M W (1999) Gene expression is altered in perfused arterial segments exposed to cyclic flexure ex vivo. Ann Biomed Eng 27:366-71
Peters, D G; Kassam, A; St Jean, P L et al. (1999) Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke 30:2612-6
Peters, D G; Kassam, A B; Yonas, H et al. (1999) Comprehensive transcript analysis in small quantities of mRNA by SAGE-lite. Nucleic Acids Res 27:e39
St Jean, P; Hart, B; Webster, M et al. (1996) Alpha-1-antitrypsin deficiency in aneurysmal disease. Hum Hered 46:92-7

Showing the most recent 10 out of 13 publications