Abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta which can, if undetected, lead to rupture. The mortality associated with ruptured AAA is estimated to be 90%, while elective repair has a mortality risk of approximately 6%. Ruptured AAA is a leading cause of death among older Americans. The identification of markers of AAA risk could lead to preventive intervention. AAA aggregates in families, and segregation analysis shows that familial risk of AAA is best explained by the segregation of a major gene with an autosomal recessive mode of inheritance. The goal of this project is to identify the genetic (major genes) and environmental factors responsible for the significant aggregation of AAA among relatives of affected individuals. This goal will be achieved by satisfying the following specific aims: 1) to collect a minimum of 180 affected relative pairs (primarily sibling pairs) with AAA and no evidence of a family history of a connective tissue disorder, and to genotype these individuals for 150 highly informative microsatellite polymorphisms marking the autosomal genome at a resolution of 20 cM; 2) to test for linkage between AAA and these loci using robust affected pedigree member methods to identify genomic regions which may contain genes that predispose individuals to develop AAA; 3) to confirm the existence of predisposing gene(s) and refine their location using a defined search strategy, genotyping at increasing levels of resolution, and re-analysis of family data; and 4) to identify the predisposing gene by a combination of saturation mapping and molecular analysis of candidate loci; and 5) to investigate the association of AAA with environmental measures to determine an equation for estimating risk for relatives of AAA patients based upon environmental measures and genotype. Power calculations based upon the number and structure of families already collected demonstrate the feasibility of identifying genes that predispose to AAA using this strategy, even in presence of significant heterogeneity with respect to the loci involved. In addition to identifying genes that are necessary for AAA by linkage analysis, a series of analyses of association will be undertaken to identify true susceptibility genes that are neither necessary nor sufficient to cause disease, but which modify an individual's risk of developing AAA.
Showing the most recent 10 out of 13 publications
