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(Circulation. 2004;109:2103-2108.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Genome Scan for Familial Abdominal Aortic Aneurysm Using Sex and Family History as Covariates Suggests Genetic Heterogeneity and Identifies Linkage to Chromosome 19q13

Hidenori Shibamura, MD, PhD; Jane M. Olson, PhD; Clarissa van Vlijmen-van Keulen, MD; Sarah G. Buxbaum, PhD; Doreen M. Dudek, MS; Gerard Tromp, PhD; Toru Ogata, MD; Magdalena Skunca, MS; Natzi Sakalihasan, MD, PhD; Gerard Pals, PhD; Raymond Limet, MD, PhD; Gerald L. MacKean, MD; Olivier Defawe, MS; Alain Verloes, MD; Claudette Arthur, BN, MBA; Alan G. Lossing, MD; Marjorie Burnett, BS; Taijiro Sueda, MD, PhD; Helena Kuivaniemi, MD, PhD

From the Center for Molecular Medicine and Genetics (H.S., G.T., T.O., M.S., H.K.) and Department of Surgery (H.K.), Wayne State University School of Medicine, Detroit, Mich; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio (J.M.O., S.G.B., D.M.D.); Departments of Vascular Surgery (C.v.V.–v.K.) and Clinical Genetics (G.P.), Free University Medical Center, Amsterdam, the Netherlands; Departments of Cardiovascular Surgery (N.S., R.L., O.D.) and Human Genetics (A.V.), University Hospital of Liège, Liège, Belgium; Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada (G.L.M., C.A.); Department of Surgery, University of Toronto, Toronto, Ontario, Canada (A.G.L., M.B.); and Department of Surgery, Hiroshima University, Hiroshima, Japan (T.S.). Dr Buxbaum is now at Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pa; Dr Verloes is now at Clinical Genetic Unit, Robert Debre Hospital, Paris, France; and Dr Shibamura is now at Department of Surgery, Hiroshima University, Hiroshima, Japan.

Correspondence to Helena Kuivaniemi, MD, PhD, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 3106 Scott Hall, 540 E Canfield Ave, Detroit, MI 48201. E-mail kuivan{at}sanger.med.wayne.edu

Received August 1, 2003; de novo received November 15, 2003; revision received January 27, 2004; accepted February 4, 2004.

Background— Abdominal aortic aneurysm (AAA) is a relatively common disease, with 1% to 2% of the population harboring aneurysms. Genetic risk factors are likely to contribute to the development of AAAs, although no such risk factors have been identified.

Methods and Results— We performed a whole-genome scan of AAA using affected-relative-pair (ARP) linkage analysis that includes covariates to allow for genetic heterogeneity. We found strong evidence of linkage (logarithm of odds [LOD] score=4.64) to a region near marker D19S433 at 51.88 centimorgans (cM) on chromosome 19 with 36 families (75 ARPs) when including sex and the number of affected first-degree relatives of the proband (N_aff) as covariates. We then genotyped 83 additional families for the same markers and typed additional markers for all families and obtained a LOD score of 4.75 (P=0.00014) with sex, N_aff, and their interaction as covariates near marker D19S416 (58.69 cM). We also identified a region on chromosome 4 with a LOD score of 3.73 (P=0.0012) near marker D4S1644 using the same covariate model as for chromosome 19.

Conclusions— Our results provide evidence for genetic heterogeneity and the presence of susceptibility loci for AAA on chromosomes 19q13 and 4q31.

Key Words: aorta • aneurysm • genetics • mapping

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