Abstract
We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10−10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10−5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10−5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases—that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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Acknowledgements
We thank the individuals who participated in the study and whose contribution made this work possible. This study was funded in part through grants from the US National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (R01HL089650-02), and from two projects in the European Community′s Seventh Framework Programme (FP7/2007-2013): the Fighting Aneurysmal Disease project grant agreement HEALTH-F2-2008-200647, and ENGAGE project grant agreement HEALTH-F4-2007-201413. The gene expression study in aorta and mammary artery was funded by the Swedish Research Council (12660) and a donation by F. Lundberg. The recruitment of AAA sample sets and controls from Belgium, Canada and Pittsburgh was funded in part by grants from the NHLBI (HL064310 to H.K. and HL044682 to R.E.F.). The Finnish IA sample collection was funded in part by the US National Institute of Neurological Disorders and Stroke (NS034395 to G. Tromp), the American Heart Association, Michigan Affiliate (to G. Tromp) and the University of Kuopio (to A.R.). A.F.B. and Y.M.R. were supported by grants from the Dr. E. Dekker program of the Netherlands Heart Foundation (2009T001 and 2005T014 respectively). New Zealand samples were recruited and genotyped through the Vascular Research Consortium of New Zealand with funding via a program grant from the Health Research Council of New Zealand. Sample collection in Danville, Pennsylvania, was funded by a grant from the American Heart Association (to D.J.C.). UK sample collection was funded partially by grants from the UK Medical Research Council and the British Heart Foundation (to J.T.P.). The recruitment of VTE patients and controls from Spain was funded in part by grants from the Instituto Carlos III (RECAVA RD06/0014/0004, RD06/0014/0039 and 06/0014/0016). DNA isolation of Dutch AAA samples was funded from a grant from the Novartis Foundation for Cardiovascular Excellence. The GeneSTAR Research Program was funded in part by the NHLBI (HL087698 to L.C.B. and HL58625 to D.M.B.). The Danish Study of control subjects was funded by research grants from the Danish Research Council, the Danish Diabetes Association, the Danish Centre for Health Technology Assessment, Novo Nordisk, the Research Foundation of Copenhagen County, the Danish Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation and the Velux foundation. The Inter99 was initiated by T.J. (principal investigator), K. Borch-Johnsen (co-principal investigator), H. Ibsen and T.F. Thomsen. The steering committee comprises the former two and C. Pisinger.
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The study was designed and results interpreted by S.G., A.F.B., H.H., G. Thorleifsson, U.T. and K.S. The first draft was written by S.G., A.F.B., H.H., G. Thorleifsson and U.T. Statistical analysis was performed by G. Thorleifsson, A.K., P.S., G. Masson and G.B.W. Expression analysis was designed and implemented by Adalbjorg Jonasdottir and Aslaug Jonasdottir. Biological material collection and handling was supervised by J.S., S.G., K.P.M. and U.T. Genotyping was supervised by S.G., M.M., J.P.K. and U.T. Collection of vessel wall biopsies and gene expression analyses in aorta and mammary artery were performed by L.F., A.F.-C. and P.E. Those responsible for patient and control ascertainment, recruitment and phenotypic information were S.E.M. and S.G. (AAA and PAD Iceland); A.F.B., M.d.H., J.-P.P.M.d.V., S.E.K., C.J.A.M.Z., S.M.v.S., R.H.G., D.E.G. and J.D.B. (AAA Utrecht, The Netherlands); G.T.J. and A.M.v.R., (AAA, PAD and controls, New Zealand); A.P.M.B. (AAA and controls, Nijmegen, The Netherlands); S.U. and J.S.L. (AAA and PAD, Denmark); N.S., R.L., J.-O.D. and H.K. (AAA and controls, Belgium); H.K. (AAA and controls, Canada); H.K. and R.E.F. (AAA, Pittsburgh); J.R.E. and D.J.C. (AAA, PAD and controls, Danville, Pennsylvania); J.T.P. (AAA, UK); T.M., B.D. and M.H. (PAD and controls, Austria); E.G. and R. Pola (PAD and controls, Italy); B.L. and A.G. (PAD and controls, Sweden); K.A. and G. Thorgeirsson (MI, Iceland); L.C.B. and D.M.B. (MI and controls, Baltimore); G.T.J. and M.J.A.W. (MI, New Zealand); S.H.S. and C.B.G. (MI, Durham, North Carolina); V. Vaccarino, R.S.P., A.M.Z. and A.A.Q. (MI, Atlanta); E.T., G. Malerba, N.M., O.O., P.F.P. and D.G. (MI and controls, Italy); M.P.R. and D.J.R. (MI, Philadelphia); I.O., M.K.M., R. Palmason, V.H. and P.T.O. (VTE, Iceland); N.L., M.F., M.R. and P.W. (VTE and controls, Canada); F.E., J.F., V. Vicente and J.C. (VTE and controls, Spain); S.G., S.S. and E.M.V. (stroke, Iceland); S.G., H.B.M. and E.M.V. (IA, Iceland); G. Tromp and A.R. (IA and controls, Finland); C.W. and Y.M.R. (IA, The Netherlands); G.B.W. and G. Thorleifsson (obesity, Iceland); V.S. (type 2 diabetes, Iceland); H.H. (hypertension, Iceland); G. Thorleifsson and H.S. (smoking, Iceland); T.R., K.K.A., J.d.G., S.H. and L.A.K. (controls, Nijmegen, The Netherlands); V.S., T.H., D.R.W., T.J., N.G. and O.P. (controls, Denmark); H.A. and A.I.L. (controls, Atlanta); and H.S. and D.A.C. (controls, UK). All authors contributed to the final version of the paper.
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Authors whose affiliations are listed as deCODE Genetics are employees of deCODE Genetics, a biotechnology company. deCODE Genetics intends to incorporate the variants described in this paper into its genetic testing services.
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Gretarsdottir, S., Baas, A., Thorleifsson, G. et al. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat Genet 42, 692–697 (2010). https://doi.org/10.1038/ng.622
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