Genome-wide approach to finding abdominal aortic aneurysm susceptibility genes in humans

Familial aggregation of abdominal aortic aneurysms (AAAs) is now widely recognized, however, susceptibility genes have not yet been identified. Our approach to find susceptibility genes has been to collect families with AAAs and to perform DNA linkage analyses to identify regions on the human chromosomes that are linked to AAAs and could harbor susceptibility genes for AAAs. We identified 233 families with at least two individuals diagnosed with AAAs. These families had 653 AAA patients and an average of 2.8 cases per family. When evaluating mode of inheritance, 167 (72%) families were consistent with autosomal recessive inheritance, whereas 58 (25%) families were consistent with autosomal dominant inheritance and in 8 families the familial aggregation could be explained by autosomal dominant inheritance with incomplete penetrance. Blood samples from 235 affected relative pairs (ARPs) and their unaffected relatives were collected for DNA isolation and the DNA used for genotyping with highly variable microsatellite markers. We included covariates in the statistical analyses to allow for genetic heterogeneity. The results for chromosomes 19g13 and 4q31 were significant with sex, number of affected first-degree relatives, and their interaction as covariates. These chromosomal regions contain many plausible candidate genes, and the future research will include more detailed analyses of these positional candidate genes.