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⇱ Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction | Nature Genetics

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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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Figure 1
Figure 2: Association of SNPs identified through the blood eosinophil count genome-wide scan with differential white blood cell counts, platelet counts and red blood.

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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

Authors and Affiliations

  1. deCODE Genetics, Sturlugata 8, Reykjavik, 101, 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, Reykjavik, 101, 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, 6006, WA, Australia

    Carolyn Williams & Philip J Thompson

  4. The Western Australian Institute of Medical Research, Perth, 6000, WA, Australia

    Carolyn Williams & Philip J Thompson

  5. The Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth, 6009, WA, Australia

    Carolyn Williams & Philip J Thompson

  6. Department of Molecular Genetics, PathWest Laboratory Medicine of Western Australia, QEII Medical Centre, Nedlands, 6009, WA, Australia

    Jennie Hui & John Beilby

  7. Western Australian Institute for Medical Research, B Block, QEII Medical Centre, The University of Western Australia, Nedlands, 6009, WA, Australia

    Jennie Hui

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

    John Beilby

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

    Nicole M Warrington & Lyle J Palmer

  10. Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, 6009, WA, Australia

    Alan James

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

    Alan James

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

    Gerard H Koppelman

  13. Centre of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, 79085, Germany

    Andrea Heinzmann, Marcus Krueger & Klaus Deichmann

  14. Department of Epidemiology, University Medical Center, University of Groningen, Groningen, 9700, RB, 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, Cologne, 50923, Germany

    Janine Altmuller & Ian P Hall

  17. Department of Life Science, Laboratory of Genomic Diversity, Sogang University, Seoul, 121-742, 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, Reykjavik, 101, 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, Puchon, 420-031, Republic of Korea

    Choon-Sik Park

  22. Department of Respitory Medicine, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, DK-2400, Denmark

    Linda M Rasmussen, Celeste Porsbjerg, Jakob W Hansen & Vibeke Backer

  23. Research Institute of Biological Psychiatry, Sct. Hans Hospital, Boserupvej 2, Roskilde, DK-4000, Denmark

    Thomas Werge

  24. Department of Medical Sciences: Inflammation, Uppsala University, Uppsala, 75105, 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, 27710, North Carolina, USA

    Svati H Shah & Christopher B Granger

  27. Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Arshed A Quyyumi, Allan I Levey & Viola Vaccarino

  28. University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, 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. Department of Mother and Child, Section of Biology and Genetics, Biology and Genetics, University of Verona, Verona, 37129, Italy

    Elisabetta Trabetti, Giovanni Malerba & Pier Franco Pignatti

  31. Department of Mother and Child, Section of Pediatrics, University of Verona, Verona, 37129, Italy

    Attilio Boner

  32. Department of Pediatrics, Bolzano Hospital, Bolzano, 39100, Italy

    Lydia Pescollderungg

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

    Domenico Girelli, Oliviero Olivieri & Nicola Martinelli

  34. The Laboratory in Mjodd, RAM, Reykjavik, 109, Iceland

    Gudmundur I Eyjolfsson

  35. Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany

    Matthias Wjst

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

    Matthias Wjst

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

    Dirkje S Postma

Authors
  1. Daniel F Gudbjartsson
  2. Unnur S Bjornsdottir
  3. Eva Halapi
  4. Anna Helgadottir
  5. Patrick Sulem
  6. Gudrun M Jonsdottir
  7. Gudmar Thorleifsson
  8. Hafdis Helgadottir
  9. Valgerdur Steinthorsdottir
  10. Hreinn Stefansson
  11. Carolyn Williams
  12. Jennie Hui
  13. John Beilby
  14. Nicole M Warrington
  15. Alan James
  16. Lyle J Palmer
  17. Gerard H Koppelman
  18. Andrea Heinzmann
  19. Marcus Krueger
  20. H Marike Boezen
  21. Amanda Wheatley
  22. Janine Altmuller
  23. Hyoung Doo Shin
  24. Soo-Taek Uh
  25. Hyun Sub Cheong
  26. Brynja Jonsdottir
  27. David Gislason
  28. Choon-Sik Park
  29. Linda M Rasmussen
  30. Celeste Porsbjerg
  31. Jakob W Hansen
  32. Vibeke Backer
  33. Thomas Werge
  34. Christer Janson
  35. Ulla-Britt Jönsson
  36. Maggie C Y Ng
  37. Juliana Chan
  38. Wing Yee So
  39. Ronald Ma
  40. Svati H Shah
  41. Christopher B Granger
  42. Arshed A Quyyumi
  43. Allan I Levey
  44. Viola Vaccarino
  45. Muredach P Reilly
  46. Daniel J Rader
  47. Michael J A Williams
  48. Andre M van Rij
  49. Gregory T Jones
  50. Elisabetta Trabetti
  51. Giovanni Malerba
  52. Pier Franco Pignatti
  53. Attilio Boner
  54. Lydia Pescollderungg
  55. Domenico Girelli
  56. Oliviero Olivieri
  57. Nicola Martinelli
  58. Bjorn R Ludviksson
  59. Dora Ludviksdottir
  60. Gudmundur I Eyjolfsson
  61. David Arnar
  62. Gudmundur Thorgeirsson
  63. Klaus Deichmann
  64. Philip J Thompson
  65. Matthias Wjst
  66. Ian P Hall
  67. Dirkje S Postma
  68. Thorarinn Gislason
  69. Jeffrey Gulcher
  70. Augustine Kong
  71. Ingileif Jonsdottir
  72. Unnur Thorsteinsdottir
  73. Kari Stefansson

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.

Corresponding authors

Correspondence to Daniel F Gudbjartsson or Kari Stefansson.

Ethics declarations

Competing interests

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

Supplementary information

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Supplementary Methods, Supplementary Tables 1–7 and Supplementary Figures 1–3 (PDF 2110 kb)

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Gudbjartsson, D., Bjornsdottir, U., Halapi, E. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41, 342–347 (2009). https://doi.org/10.1038/ng.323

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