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Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Nature Genetics volume 41, pages 342347 (2009) | Download Citation

Abstract

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 × 10−14, 5.4 × 10−10, 8.6 × 10−17, 1.2 × 10−10 and 6.5 × 10−19, respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 × 10−12) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 × 10−6, 2.2 × 10−5 and 2.4 × 10−4, respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 × 10−8) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

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Acknowledgements

The genotyping of some of the myocardial infarction sample sets was funded in part through a grant from the US National Heart, Lung, and Blood Institute (SR01HL089650-01). The New Zealand cohort study was supported by a programme grant from the Health Research Council of New Zealand. The Korean study was supported by a grant from the Korean Health 21 R&D project, Ministry of Health & Welfare, Republic of Korea (A010249).

Author information

Affiliations

  1. deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.

    • Daniel F Gudbjartsson
    • , Unnur S Bjornsdottir
    • , Eva Halapi
    • , Anna Helgadottir
    • , Patrick Sulem
    • , Gudrun M Jonsdottir
    • , Gudmar Thorleifsson
    • , Hafdis Helgadottir
    • , Valgerdur Steinthorsdottir
    • , Hreinn Stefansson
    • , Jeffrey Gulcher
    • , Augustine Kong
    • , Ingileif Jonsdottir
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  2. Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.

    • Unnur S Bjornsdottir
    • , Bjorn R Ludviksson
    • , David Arnar
    • , Gudmundur Thorgeirsson
    • , Thorarinn Gislason
    • , Ingileif Jonsdottir
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  3. The Lung Institute of Western Australia, Nedlands WA 6006, Australia.

    • Carolyn Williams
    •  & Philip J Thompson
  4. The Western Australian Institute of Medical Research, Perth WA 6000, Australia.

    • Carolyn Williams
    •  & Philip J Thompson
  5. The Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth WA 6009, Australia.

    • Carolyn Williams
    •  & Philip J Thompson
  6. Department of Molecular Genetics, PathWest Laboratory Medicine of Western Australia, QEII Medical Centre, Nedlands WA 6009, Australia.

    • Jennie Hui
    •  & John Beilby
  7. Western Australian Institute for Medical Research, B Block, QEII Medical Centre, The University of Western Australia, Nedlands WA 6009, Australia.

    • Jennie Hui
  8. School of Surgery and Pathology, University of Western Australia, Perth WA 6009, Australia.

    • John Beilby
  9. Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Perth WA 6009, Australia.

    • Nicole M Warrington
    •  & Lyle J Palmer
  10. West Australian Sleep Disorders Research Institute, Department of Pulmonary Physiology, Sir Charles Gairdner Hospital, Nedlands WA 6009, Australia.

    • Alan James
  11. School of Medicine and Pharmacology, The University of Western Australia, Nedlands WA 6009, Australia.

    • Alan James
  12. Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

    • Gerard H Koppelman
  13. Centre of Pediatrics and Adolescent Medicine, University of Freiburg, 79085 Freiburg, Germany.

    • Andrea Heinzmann
    • , Marcus Krueger
    •  & Klaus Deichmann
  14. Department of Epidemiology, University Medical Center, University of Groningen, 9700 RB Groningen, The Netherlands.

    • H Marike Boezen
  15. Division of Therapeutics, University Hospital of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.

    • Amanda Wheatley
  16. Cologne Center for Genomics, University of Cologne, 50923 Cologne, Germany.

    • Janine Altmuller
    •  & Ian P Hall
  17. Laboratory of Genomic Diversity, Department of Life Science, Sogang University, Seoul121-742, Republic of Korea.

    • Hyoung Doo Shin
  18. Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul 153-803, Republic of Korea.

    • Hyoung Doo Shin
  19. Division of Allergy and Respiratory Medicine, Soonchunhyang University Seoul Hospital, 140-210 Seoul, Republic of Korea.

    • Soo-Taek Uh
    •  & Hyun Sub Cheong
  20. Landspitali University Hospital, 101 Reykjavik, Iceland.

    • Brynja Jonsdottir
    • , David Gislason
    • , Bjorn R Ludviksson
    • , Dora Ludviksdottir
    • , David Arnar
    • , Gudmundur Thorgeirsson
    • , Thorarinn Gislason
    •  & Ingileif Jonsdottir
  21. Division of Allergy and Respiratory Medicine, Soonchunhyang University, Bucheon Hospital, 420-031 Puchon, Republic of Korea.

    • Choon-Sik Park
  22. Department of Respitory Medicine, Bispebjerg Hospital, Copenhagen University Hospital, DK-2400 Copenhagen, Denmark.

    • Linda M Rasmussen
    • , Celeste Porsbjerg
    • , Jakob W Hansen
    •  & Vibeke Backer
  23. Research Institute of Biological Psychiatry, Sct. Hans Hospital, Boserupvej 2, DK-4000 Roskilde, Denmark.

    • Thomas Werge
  24. Department of Medical Sciences: Inflammation, Uppsala University, 75105 Uppsala, Sweden.

    • Christer Janson
    •  & Ulla-Britt Jönsson
  25. Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.

    • Maggie C Y Ng
    • , Juliana Chan
    • , Wing Yee So
    •  & Ronald Ma
  26. Duke University School of Medicine, Durham, North Carolina 27710, USA.

    • Svati H Shah
    •  & Christopher B Granger
  27. Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Arshed A Quyyumi
    • , Allan I Levey
    •  & Viola Vaccarino
  28. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Muredach P Reilly
    •  & Daniel J Rader
  29. Vascular Research Group, Otago Medical School, PO Box 913, Dunedin 9054, New Zealand.

    • Michael J A Williams
    • , Andre M van Rij
    •  & Gregory T Jones
  30. Section of Biology and Genetics, Department of Mother and Child, Biology and Genetics, University of Verona, 37129 Verona, Italy.

    • Elisabetta Trabetti
    • , Giovanni Malerba
    •  & Pier Franco Pignatti
  31. Section of Pediatrics, Department of Mother and Child, University of Verona, 37129 Verona, Italy.

    • Attilio Boner
  32. Department of Pediatrics, Bolzano Hospital, 39100 Bolzano, Italy.

    • Lydia Pescollderungg
  33. Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, 37129 Verona, Italy.

    • Domenico Girelli
    • , Oliviero Olivieri
    •  & Nicola Martinelli
  34. The Laboratory in Mjodd, RAM, 109 Reykjavik, Iceland.

    • Gudmundur I Eyjolfsson
  35. Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

    • Matthias Wjst
  36. Institute of Genetic Medicine, EURAC Research, 39100 Bozen, Germany.

    • Matthias Wjst
  37. Department of Pulmonology, University Medical Center, University of Groningen, 9700 RB Groningen, The Netherlands.

    • Dirkje S Postma

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Contributions

D.F.G., U.S.B., M.W., I.P.H., D.S.P., I.J., U.T. and K.S. wrote the first draft of the paper. U.S.B., E.H., A. Helgadottir, B.J., D. Gislason, B.R.L., D.L., G.I.E., D.A. and G. Thorgeirsson participated in the collection of the Icelandic data. C.W., J.H., J.B., N.M.W., A.J., L.J.P. and P.J.T. collected the Australian data. G.H.K., H.M.B. and D.S.P. collected the Dutch data. A. Heinzmann, M.K., J.A.,K.D. and M.W. collected the German data. A.W. and I.P.H. collected the UK data. H.D.S., S.-T.U., H.S.C. and C.-S.P. collected the Korean data. L.M.R., C.P., J.W.H., V.B. and T.W. collected the Danish data. C.J. and U.-B.J. collected the Swedish data. M.C.Y.N., J.C., W.Y.S. and R.M. collected the Hong Kong data. S.H.S., C.B.G, A.A.Q., A.I.L., V.V., M.P.R. and D.J.R. collected the US data. M.J.A.W., A.M.V.R. and G.T.J. collected the New Zealand data. E.T., G.M., P.F.P., A.B., L.P., D. Girelli, O.O. and N.M. collected the Italian data. E.H., A. Helgadottir, H.H., V.S. and U.T. carried out the genotyping. D.F.G., P.S., G.M.J., G. Thorleifsson, H.S. and A.K. analyzed the data. D.F.G., U.S.B., K.D., P.J.T., M.W., I.P.H., D.S.P., T.G., J.G., I.J., U.T. and K.S. planned and supervised the work. All authors contributed to the final version of the paper.

Competing interests

The authors from deCODE own stocks and stock options in the company.

Corresponding authors

Correspondence to Daniel F Gudbjartsson or Kari Stefansson.

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DOI

https://doi.org/10.1038/ng.323

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