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. ? ?
| Telomeres Mendelian Randomization Collaboration; Haycock, Philip C; Burgess, Stephen et al. (2017) Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. JAMA Oncol 3:636-651 |
| Kuivaniemi, Helena; Ryer, Evan J; Elmore, James R et al. (2015) Understanding the pathogenesis of abdominal aortic aneurysms. Expert Rev Cardiovasc Ther 13:975-87 |
| Hinterseher, Irene; Schworer, Charles M; Lillvis, John H et al. (2015) Immunohistochemical analysis of the natural killer cell cytotoxicity pathway in human abdominal aortic aneurysms. Int J Mol Sci 16:11196-212 |
| Pahl, Matthew C; Erdman, Robert; Kuivaniemi, Helena et al. (2015) Transcriptional (ChIP-Chip) Analysis of ELF1, ETS2, RUNX1 and STAT5 in Human Abdominal Aortic Aneurysm. Int J Mol Sci 16:11229-58 |
| Kuivaniemi, Helena; Ryer, Evan J; Elmore, James R et al. (2014) Update on abdominal aortic aneurysm research: from clinical to genetic studies. Scientifica (Cairo) 2014:564734 |
| Sakalihasan, Natzi; Defraigne, Jean-Olivier; Kerstenne, Marie-Ange et al. (2014) Family members of patients with abdominal aortic aneurysms are at increased risk for aneurysms: analysis of 618 probands and their families from the Liège AAA Family Study. Ann Vasc Surg 28:787-97 |
| Jones, Gregory T; Bown, Matthew J; Gretarsdottir, Solveig et al. (2013) A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm. Hum Mol Genet 22:2941-7 |
| Golledge, Jonathan; Kuivaniemi, Helena (2013) Genetics of abdominal aortic aneurysm. Curr Opin Cardiol 28:290-6 |
| Hinterseher, Irene; Erdman, Robert; Elmore, James R et al. (2013) Novel pathways in the pathobiology of human abdominal aortic aneurysms. Pathobiology 80:1-10 |
| Pahl, Matthew C; Derr, Kimberly; Gabel, Gabor et al. (2012) MicroRNA expression signature in human abdominal aortic aneurysms. BMC Med Genomics 5:25 |
Showing the most recent 10 out of 41 publications
