This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Familial aggregation of abdominal aortic aneurysms (AAA) is widely recognized. AAA patients with a family history are significantly younger than sporadic AAA cases at the time of diagnosis and familial cases are more likely to rupture. The sibling relative risk has been estimated to be about 15 - 20. Sporadic cases show a 6:1 male: female ratio, while in familial cases the ratio is 2:1. Affected relative pairs are identified by first identifying a proband with AAA, obtaining family history, and offering abdominal ultrasonography examination to first-degree relatives to detect asymptomatic AAAs. As a result, and because of the high mortality for ruptured AAA, collection of AAA families is slow, expensive, and requires extraordinary effort. The genome scan on the initial set of affected sib pairs is expected to be completed within the next year. To date, DNA from 65 affected sib pairs from the US, Canada, and Belgium has been collected and has been genotyped for a genome scan by the Mammalian Genotyping Service. Initial analysis reveals the strongest linkage (lod = 4.57, with one covariate) on chromosome 19, particularly in families with larger numbers of affected relatives. An additional 120 affected sib pairs have been collected and have been genotyped for chromosome 19 markers. Analysis of the replicate sample confirms linkage to chromosome 19 (lod score = 4.26, with a covariate). Analysis of the combined data set gives a lod score of 4.98, with one covariate; the results suggest that families with larger numbers of affected individuals that include at least one female affected are the most likely linked. We plan to pursue fine mapping strategies on this linked subgroup. We also plan to complete the genome scan on the new set of families.
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