Letter | Published:

Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm

Nature Genetics volume 42, pages 692697 (2010) | Download Citation

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.

Author information

Author notes

    • Solveig Gretarsdottir
    • , Annette F Baas
    • , Gudmar Thorleifsson
    •  & Hilma Holm

    These authors contributed equally to this work.

Affiliations

  1. Population Genomics, deCODE Genetics, Reykjavik, Iceland.

    • Solveig Gretarsdottir
    • , Gudmar Thorleifsson
    • , Hilma Holm
    • , Jelena P Kostic
    • , Adalbjorg Jonasdottir
    • , Aslaug Jonasdottir
    • , G Bragi Walters
    • , Gisli Masson
    • , Patrick Sulem
    • , Jona Saemundsdottir
    • , Magali Mouy
    • , Hreinn Stefansson
    • , Valgerdur Steinthorsdottir
    • , Thorunn Rafnar
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  2. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Annette F Baas
  3. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Annette F Baas
    •  & Diederick E Grobbee
  4. Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Martin den Heijer
    • , Katja K Aben
    •  & Lambertus A Kiemeney
  5. Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Martin den Heijer
  6. Department of Vascular Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.

    • Jean-Paul P M de Vries
  7. Department of Surgery, TweeSteden hospital Tilburg, Tilburg, The Netherlands.

    • Steef E Kranendonk
  8. Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands.

    • Clark J A M Zeebregts
  9. Department of Surgery, Division of Vascular Surgery, Alysis Zorggroep, Location Rijnstate, Arnhem, The Netherlands.

    • Steven M van Sterkenburg
  10. Department of Surgery, Medical Spectrum Twente, Enschede, The Netherlands.

    • Robert H Geelkerken
  11. Department of Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

    • Andre M van Rij
    •  & Gregory T Jones
  12. Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

    • Michael J A Williams
  13. Department of Surgery, Canisius Wilhelmina Hospital Nijmegen, Nijmegen, The Netherlands.

    • Albert P M Boll
  14. University of Akureyri, Borgir vid Nordurslod, Akureyri, Iceland.

    • Kristinn P Magnusson
  15. Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, USA.

    • Gerard Tromp
    • , David J Carey
    •  & Helena Kuivaniemi
  16. Department of Vascular Surgery, Geisinger Clinic, Danville, Pennsylvania, USA.

    • James R Elmore
  17. University of Liège, Liège, Belgium.

    • Natzi Sakalihasan
    • , Raymond Limet
    •  & Jean-Olivier Defraigne
  18. Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.

    • Robert E Ferrell
  19. Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.

    • Antti Ronkainen
  20. Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Ynte M Ruigrok
  21. Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

    • Cisca Wijmenga
  22. Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA.

    • Svati H Shah
  23. Department of Medicine and Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA.

    • Christopher B Granger
  24. Emory University School of Medicine, Atlanta, Georgia, USA.

    • Arshed A Quyyumi
    • , Viola Vaccarino
    • , Riyaz S Patel
    • , A Maziar Zafari
    •  & Allan I Levey
  25. Cardiff University, Cardiff, UK.

    • Riyaz S Patel
  26. Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.

    • A Maziar Zafari
  27. Emory University School of Public Health, Atlanta, Georgia, USA.

    • Harland Austin
  28. Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy.

    • Domenico Girelli
    • , Oliviero Olivieri
    •  & Nicola Martinelli
  29. Department of Life and Reproduction Sciences, Section of Biology and Genetics, University of Verona, Verona, Italy.

    • Pier Franco Pignatti
    • , Giovanni Malerba
    •  & Elisabetta Trabetti
  30. The Johns Hopkins GeneSTAR Research Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Lewis C Becker
    •  & Diane M Becker
  31. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Muredach P Reilly
    •  & Daniel J Rader
  32. Department of Laboratory Medicine, Konventhospital Barmherzige Brueder, Linz, Austria.

    • Thomas Mueller
    • , Benjamin Dieplinger
    •  & Meinhard Haltmayer
  33. Vascular Research Unit, Viborg Hospital, Viborg, Denmark.

    • Sigitas Urbonavicius
    •  & Jes S Lindholt
  34. Vascular Center, Skaane University Hospital, Malmö, Sweden.

    • Bengt Lindblad
    •  & Anders Gottsäter
  35. Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy.

    • Eleonora Gaetani
    •  & Roberto Pola
  36. Division of Cardiovascular Research, Department of Medicine, Caritas St. Elizabeth′s Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • Roberto Pola
  37. Department of Medicine ,The Ottawa Hospital, Ottawa, Ontario, Canada.

    • Philip Wells
  38. Division of Hematology, The Ottawa Hospital, Ottawa, Ontario, Canada.

    • Marc Rodger
  39. Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

    • Melissa Forgie
  40. Clinical Epidemiology, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

    • Nicole Langlois
  41. Department of Medicine, University of Murcia, Centro Regional de Hemodonación, Murcia, Spain.

    • Javier Corral
    •  & Vicente Vicente
  42. Hemostasia and Thrombosis Unit, Santa Creu i Sant Pau Hospital, Barcelona, Spain.

    • Jordi Fontcuberta
  43. Research Center, La Fé Hospital, Valencia, Spain.

    • Francisco España
  44. Hagedorn Research Institute, Gentofte, Denmark.

    • Niels Grarup
    • , Torben Hansen
    •  & Oluf Pedersen
  45. Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark.

    • Torben Jørgensen
  46. Faculty of Health Sciences, University of Copenhagen, Denmark.

    • Torben Jørgensen
  47. Steno Diabetes Center, Gentofte, Denmark.

    • Daniel R Witte
  48. University of Southern Denmark, Odense, Denmark.

    • Torben Hansen
  49. Institute of Biomedical Sciences, University of Copenhagen, Denmark.

    • Oluf Pedersen
  50. Comprehensive Cancer Centre East, Nijmegen, The Netherlands.

    • Katja K Aben
  51. Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Jacqueline de Graaf
    •  & Suzanne Holewijn
  52. Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Lasse Folkersen
    •  & Per Eriksson
  53. Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Anders Franco-Cereceda
  54. Division of Psychological Medicine and Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

    • David A Collier
  55. Landspitali University Hospital, Reykjavik, Iceland.

    • Einar M Valdimarsson
    • , Sigurlaug Sveinbjornsdottir
    • , Isleifur Olafsson
    • , Magnus Karl Magnusson
    • , Robert Palmason
    • , Vilhelmina Haraldsdottir
    • , Karl Andersen
    • , Pall T Onundarson
    •  & Gudmundur Thorgeirsson
  56. Upper Valley Neurology Neurosurgery, Lebanon, New Hampshire, USA.

    • Hulda B Magnadottir
  57. University of Iceland, Faculty of Medicine, Reykjavik, Iceland.

    • Magnus Karl Magnusson
    • , Vilhelmina Haraldsdottir
    • , Karl Andersen
    • , Pall T Onundarson
    • , Gudmundur Thorgeirsson
    • , Stefan E Matthiasson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  58. Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  59. Imperial College at Charing Cross, London, UK.

    • Janet T Powell
  60. Division of Surgery, VU Medical Center Amsterdam, Amsterdam, The Netherlands.

    • Jan D Blankensteijn
  61. Department of Vascular Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Jan D Blankensteijn

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Contributions

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.

Competing interests

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.

Corresponding authors

Correspondence to Solveig Gretarsdottir or Kari Stefansson.

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DOI

https://doi.org/10.1038/ng.622

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