Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

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).

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Hogan, S.P. et al. Eosinophils: biological properties and role in health and disease. Clin. Exp. Allergy 38, 709–750 (2008).

    Article  CAS  Google Scholar 

  2. Lee, J.J. et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305, 1773–1776 (2004).

    Article  CAS  Google Scholar 

  3. International Hap Map Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  4. Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).

    Article  CAS  Google Scholar 

  5. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl. Acad. Sci. USA 104, 282–287 (2007).

    Article  CAS  Google Scholar 

  6. Cherry, W.B., Yoon, J., Bartemes, K.R., Iijima, K. & Kita, H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J. Allergy Clin. Immunol. 121, 1484–1490 (2008).

    Article  CAS  Google Scholar 

  7. Zhernakova, A. et al. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am. J. Hum. Genet. 82, 1202–1210 (2008).

    Article  CAS  Google Scholar 

  8. Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

    Article  CAS  Google Scholar 

  9. Shimizu, M. et al. Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis. Hum. Mol. Genet. 14, 2919–2927 (2005).

    Article  CAS  Google Scholar 

  10. Zhu, G. et al. Interleukin 18 receptor 1 gene polymorphisms are associated with asthma. Eur. J. Hum. Genet. 16, 1083–1090 (2008).

    Article  CAS  Google Scholar 

  11. Reijmerink, N.E. et al. Association of IL1RL1, IL18R1, and IL18RAP gene cluster polymorphisms with asthma and atopy. J. Allergy Clin. Immunol. 122, 651–654 (2008).

    Article  Google Scholar 

  12. Mao, M. et al. T lymphocyte activation gene identification by coregulated expression on DNA microarrays. Genomics 83, 989–999 (2004).

    Article  CAS  Google Scholar 

  13. Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6, 1047–1053 (2005).

    Article  CAS  Google Scholar 

  14. Ying, S. et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol. 174, 8183–8190 (2005).

    Article  CAS  Google Scholar 

  15. Thein, S.L. et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc. Natl. Acad. Sci. USA 104, 11346–11351 (2007).

    Article  CAS  Google Scholar 

  16. Menzel, S. et al. The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood 110, 3624–3626 (2007).

    Article  CAS  Google Scholar 

  17. Martinez-Moczygemba, M. & Huston, D.P. Biology of common β receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J. Allergy Clin. Immunol. 112, 653–665 (2003).

    Article  CAS  Google Scholar 

  18. Thorgeirsson, T.E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).

    Article  CAS  Google Scholar 

  19. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  20. Todd, J.A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2007).

    Article  CAS  Google Scholar 

  21. Velazquez, L. et al. Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J. Exp. Med. 195, 1599–1611 (2002).

    Article  CAS  Google Scholar 

  22. Hirasawa, R. et al. Essential and instructive roles of GATA factors in eosinophil development. J. Exp. Med. 195, 1379–1386 (2002).

    Article  CAS  Google Scholar 

  23. Iwasaki, H. et al. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev. 20, 3010–3021 (2006).

    Article  CAS  Google Scholar 

  24. Rebollo, A. & Schmitt, C. Ikaros, Aiolos and Helios: transcription regulators and lymphoid malignancies. Immunol. Cell Biol. 81, 171–175 (2003).

    Article  CAS  Google Scholar 

  25. Gudbjartsson, D.F. et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat. Genet. 40, 886–891 (2008).

    Article  CAS  Google Scholar 

  26. Vitart, V. et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat. Genet. 40, 437–442 (2008).

    Article  CAS  Google Scholar 

  27. Devlin, B., Bacanu, S.A. & Roeder, K. Genomic Control to the extreme. Nat. Genet. 36, 1129–1130 (2004).

    Article  CAS  Google Scholar 

  28. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    Article  CAS  Google Scholar 

Download references

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

Authors

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

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing