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.

Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis

Nature Genetics volume 44, pages 522–525 (2012)Cite this article

Subjects

Abstract

To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10−8). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Results of genome-wide association analysis (−log10 P) shown in chromosomal order for 716,935 SNPs tested for association in initial sample of 622 Kawasaki disease cases and 1,107 controls.
Figure 2: Association plots for the BLK and CD40 regions.

References

  1. Kato, H., Koike, S., Yamamoto, M., Ito, Y. & Yano, E. Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome. J. Pediatr. 86, 892–898 (1975).

    Article  CAS  PubMed  Google Scholar 

  2. Kato, H. et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 94, 1379–1385 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Yanagawa, H. et al. Results of the nationwide epidemiologic survey of Kawasaki disease in 1995 and 1996 in Japan. Pediatrics 102, E65 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Yanagawa, H. et al. Incidence survey of Kawasaki disease in 1997 and 1998 in Japan. Pediatrics 107, E33 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Park, Y.W. et al. Epidemiological features of Kawasaki disease in Korea, 2006–2008. Pediatr. Int. 53, 36–39 (2011).

    Article  PubMed  Google Scholar 

  6. Chang, L.Y. et al. Epidemiologic features of Kawasaki disease in Taiwan, 1996–2002. Pediatrics 114, e678–e682 (2004).

    Article  PubMed  Google Scholar 

  7. Huang, W.C. et al. Epidemiologic features of Kawasaki disease in Taiwan, 2003–2006. Pediatrics 123, e401–e405 (2009).

    Article  PubMed  Google Scholar 

  8. Matsubara, T., Furukawa, S. & Yabuta, K. Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-γ in Kawasaki disease involved coronary-artery lesions. Clin. Immunol. Immunopathol. 56, 29–36 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Lin, C.Y., Lin, C.C., Hwang, B. & Chiang, B. Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor α among patients with Kawasaki disease. J. Pediatr. 121, 924–926 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Onouchi, Y. Molecular genetics of Kawasaki disease. Pediatr. Res. 65, 46R–54R (2009).

    Article  PubMed  Google Scholar 

  11. Onouchi, Y. et al. A genomewide linkage analysis of Kawasaki disease: evidence for linkage to chromosome 12. J. Hum. Genet. 52, 179–190 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Onouchi, Y. et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat. Genet. 40, 35–42 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Burgner, D. et al. A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet. 5, e1000319 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kim, J.J. et al. A genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for Kawasaki disease. Hum. Genet. 129, 487–495 (2011).

    Article  PubMed  Google Scholar 

  15. Tsai, F.J. et al. Identification of novel susceptibility loci for Kawasaki disease in a Han Chinese population by a genome-wide association study. PLoS ONE 6, e16853 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Khor, C.C. et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat. Genet. 43, 1241–1246 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Dymecki, S.M., Zwollo, P., Zeller, K., Kuhajda, F.P. & Desiderio, S.V. Structure and developmental regulation of the B-lymphoid tyrosine kinase gene blk. J. Biol. Chem. 267, 4815–4823 (1992).

    CAS  PubMed  Google Scholar 

  18. Wasserman, R., Li, Y.S. & Hardy, R.R. Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. J. Immunol. 155, 644–651 (1995).

    CAS  PubMed  Google Scholar 

  19. Nemazee, D. & Weigert, M. Revising B cell receptors. J. Exp. Med. 191, 1813–1817 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Gregersen, P.K. et al. REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat. Genet. 41, 820–823 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Peters, A.L., Stunz, L.L. & Bishop, G.A. CD40 and autoimmunity: the dark side of a great activator. Semin. Immunol. 21, 293–300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Akiyama, T. et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423–437 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Iezzi, G. et al. CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17–producing CD4+ T cells. Proc. Natl. Acad. Sci. USA 106, 876–881 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jacobson, E.M. et al. A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression. Genes Immun. 8, 205–214 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Wagner, D.H. Jr. et al. Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes. Proc. Natl. Acad. Sci. USA 99, 3782–3787 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gerritse, K. et al. CD40–CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc. Natl. Acad. Sci. USA 93, 2499–2504 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ohta, Y. & Hamada, Y. In situ expression of CD40 and CD40 ligand in psoriasis. Dermatology 209, 21–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Danese, S. et al. TNF-α blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease. J. Immunol. 176, 2617–2624 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Brennan, F.M. & McInnes, I.B. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 118, 3537–3545 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pyrovolaki, K. et al. Increased expression of CD40 on bone marrow CD34+ hematopoietic progenitor cells in patients with systemic lupus erythematosus: contribution to Fas-mediated apoptosis. Arthritis Rheum. 60, 543–552 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Tomer, Y., Concepcion, E. & Greenberg, D.A. A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves' disease. Thyroid 12, 1129–1135 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Ban, Y., Tozaki, T., Taniyama, M. & Tomita, M. Association of a C/T single-nucleotide polymorphism in the 5′ untranslated region of the CD40 gene with Graves' disease in Japanese. Thyroid 16, 443–446 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Kurylowicz, A. et al. Association of CD40 gene polymorphism (C-1T) with susceptibility and phenotype of Graves' disease. Thyroid 15, 1119–1124 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Blanco-Kelly, F. et al. CD40: novel association with Crohn's disease and replication in multiple sclerosis susceptibility. PLoS ONE 5, e11520 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Law, C.L. & Grewal, I.S. Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges. Adv. Exp. Med. Biol. 647, 8–36 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Hassan, G.S., Merhi, Y. & Mourad, W.M. CD154 and its receptors in inflammatory vascular pathologies. Trends Immunol. 30, 165–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, C.L. et al. Expression of CD40 ligand on CD4+ T-cells and platelets correlated to the coronary artery lesion and disease progress in Kawasaki disease. Pediatrics 111, E140–E147 (2003).

    Article  PubMed  Google Scholar 

  40. Newburger, J.W. et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 114, 1708–1733 (2004).

    Article  PubMed  Google Scholar 

  41. Kim, S. & Dedeoglu, F. Update on pediatric vasculitis. Curr. Opin. Pediatr. 17, 695–702 (2005).

    Article  PubMed  Google Scholar 

  42. Pan, W.H. et al. Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations. Hum. Hered. 61, 27–30 (2006).

    Article  PubMed  Google Scholar 

  43. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all affected individuals and their families who devoted their time and effort to participate in this study. We gratefully acknowledge the members of the Translational Resource Center (TRC) (NSC100-2325-B-001-023) for Genomic Medicine and the National Center for Genome Medicine (NCGM) (NSC100-2319-B-001-001) at Academia Sinica for their support in subject recruitment, genotyping and statistical analysis. We especially thank H. Lue for his inspirational discussion. This study was supported by the Academia Sinica Genomic Medicine Multicenter Study, Taiwan (40-05-GMM). The funders had no role in study design, data collection or analysis, the decision to publish or preparation of the manuscript.

Author information

Author notes

  1. Taiwan Pediatric ID Alliance and Fuu-Jen Tsai: A complete list of members and affiliations appears in the Supplementary Note.

  2. Yi-Ching Lee, Ho-Chang Kuo, Jeng-Sheng Chang and Luan-Yin Chang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Yi-Ching Lee, Li-Ching Chang, Yi-Min Liu, Ying-Ju Chen, Chien-Hsiun Chen, Yuan-Tsong Chen & Jer-Yuarn Wu

  2. Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan

    Yi-Ching Lee

  3. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

    Ho-Chang Kuo, Chi-Di Liang & Kao-Pin Hwang

  4. Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Ho-Chang Kuo & Chi-Di Liang

  5. Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan

    Jeng-Sheng Chang

  6. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

    Luan-Yin Chang & Li-Min Huang

  7. Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan

    Ming-Ren Chen, Hsin Chi, Fu-Yuan Huang & Nan-Chang Chiu

  8. Department of Pediatrics and Divisions of Pediatric Cardiology, Changhua Christian Hospital, Changhua, Taiwan

    Meng-Luen Lee

  9. Division of Pediatric Infectious Diseases, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Yhu-Chering Huang

  10. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Yhu-Chering Huang

  11. Department of Pediatrics, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan

    Betau Hwang

  12. Department of Pediatrics, Division of Pediatric Infectious Diseases, China Medical University Hospital, Taichung, Taiwan

    Kao-Pin Hwang

  13. School of Chinese Medicine, China Medical University, Taichung, Taiwan

    Kao-Pin Hwang, Chien-Hsiun Chen, Fuu-Jen Tsai & Jer-Yuarn Wu

  14. Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan

    Pi-Chang Lee

  15. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA

    Yuan-Tsong Chen

  16. Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan

    Fuu-Jen Tsai

  17. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

    Fuu-Jen Tsai

Authors
  1. Yi-Ching Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ho-Chang Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeng-Sheng Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luan-Yin Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Min Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming-Ren Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chi-Di Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hsin Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fu-Yuan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Meng-Luen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yhu-Chering Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Betau Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nan-Chang Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kao-Pin Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Pi-Chang Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Li-Ching Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yi-Min Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Ying-Ju Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Chien-Hsiun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Taiwan Pediatric ID Alliance
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Yuan-Tsong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Fuu-Jen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Jer-Yuarn Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.-T.C., F.-J.T. and J.-Y.W. are the principal investigators who conceived and obtained funding for this project. Y.-C.L., C.-H.C. and J.-Y.W. organized and supervised the GWAS and replication genotyping pipeline and devised the overall analysis plan. Y.-C.L. wrote the first draft of the manuscript with input from C.-H.C. and J.-Y.W. Y.-C.L., L.-C.C. and C.-H.C. analyzed the data. C.-D.L., J.-S.C., L.-Y.C., L.-M.H., M.-R.C., H.-C.K., H.C., F.-Y.H., M.-L.L., Y.-C.H., B.H., N.-C.C., K.-P.H., P.-C.L., Y.-M.L., Y.-J.C. and the Taiwan Pediatric ID Alliance coordinated and contributed subject and database phenotype collections.

Corresponding authors

Correspondence to Yuan-Tsong Chen, Fuu-Jen Tsai or Jer-Yuarn Wu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–5 and Supplementary Tables 1–9 (PDF 1847 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee, YC., Kuo, HC., Chang, JS. et al. Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat Genet 44, 522–525 (2012). https://doi.org/10.1038/ng.2227

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2227

This article is cited by

Search

Advanced 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