Estimated 1-2% of the population harbor abdominal aortic aneurysms (AAA). AAAs are the 13th leading cause of death in the USA with approximately 15,000 deaths/year. Familial aggregation of AAA is widely recognized and two segregation studies suggest a major gene effect. In this application, our goal is to identify the AAA susceptibility gene(s). To date, we have identified 233 multiplex AAA families and DNA samples have been collected from approximately 250 affected sib pairs (ASPs) and their relatives for this study. A whole genome scan was performed with 65 ASPs using 402 highly polymorphic markers located on average 10 cM apart and twelve regions on eight chromosomes gave led scores which exceeded the set threshold led score of 0.8 (p<0.05) when using covariate analyses. The highest led score was 4.6 near the marker D19S433 in multipoint analysis using sex and the number of affected first-degree relatives as covariates. In the second stage of phase I we genotyped 16 additional microsatellite markers from the region on chromosome 19 and also used DNA from 121 additional ASPs and obtained a lod score of 3.07 (a pointwise p-value of 0.002) in the same model. We propose to continue the study to identify the susceptibility gene(s) for AAA. Specifically, we propose to: 1) Carry out a whole-genome scan with 300 ASPs; 2) Analyze the genome scan data for genetic linkage and identify genetically homogenous subsets of AAA ASPs linked to different sets of loci; 3) Perform follow-up fine mapping conditional on results of linkage analysis; and 4) Identify putative candidate genes on all the candidate intervals and search for sequence variations in them. At present, the most promising region is on chromosome 19, which gave the highest led score in the first genome scan, contains important candidate genes, and appears also linked to familial intracranial aneurysms. The results obtained in these studies are likely to yield important information about genetic factors contributing to the development of AAA, and could provide the basis for genetic testing to identify individuals harboring AAA before the rupture of the AAA occurs and leads to sudden death. Identification of the AAA susceptibility gene(s) will also allow us to develop animal models in future studies for testing new therapies. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064310-06
Application #
6786712
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Wassef, Momtaz K
Project Start
1999-09-30
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
6
Fiscal Year
2004
Total Cost
$379,087
Indirect Cost
Name
Wayne State University
Department
Genetics
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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