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CTLA-4, Position 49 A/G Polymorphism Associated with Coronary Artery Lesions in Kawasaki Disease

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Abstract

Objective

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology and primarily affects children less than 5 years of age. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. This study examined the correlation of CTLA-4 gene polymorphisms in KD with and without coronary artery lesions (CAL).

Materials and methods

A total of 233 KD patients and 644 controls were subjected to determination of CTLA-4 polymorphisms at (−318) C/T and (+49) A/G positions by restriction fragment length polymorphism. Susceptibility, CAL, and intravenous immunoglobulin treatment response of KD were then analyzed with genetic variants.

Results

Polymorphisms of CTLA-4 (+49 A/G) and (−318 C/T) were not significantly different between normal children and patients with KD. The CTLA-4 (+49) A allele (AA+AG genotype), however, was significantly associated with CAL formation, especially in female patients.

Conclusions

This study provides the first evidence supporting the association of CTLA-4 (+49) A/G polymorphism with the CAL formation of KD particularly in female patients.

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Abbreviations

KD:

Kawasaki disease

IVIG:

Intravenous immunoglobulin

CAL:

Coronary artery lesions

CTLA-4:

Cytotoxic T lymphocyte antigen-4

References

  1. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54:271–6.

    PubMed  CAS  Google Scholar 

  2. Wang CL, Wu YT, Liu CA, Kuo HC, Yang KD. Kawasaki disease: infection, immunity and genetics. Pediatr Infect Dis J. 2005;24:998–1004.

    Article  PubMed  Google Scholar 

  3. Burns JC, Glode MP. Kawasaki syndrome. Lancet. 2004;364:533–44.

    Article  PubMed  Google Scholar 

  4. Park YW, Han JW, Park IS, Kim CH, Cha SH, Ma JS, et al. Kawasaki disease in Korea, 2003–2005. Pediatr Infect Dis J. 2007;26:821–3.

    Article  PubMed  Google Scholar 

  5. Huang WC, Huang LM, Chang IS, Chang LY, Chiang BL, Chen PJ, et al. Epidemiologic features of Kawasaki disease in Taiwan, 2003–2006. Pediatrics. 2009;123:e401–5.

    Article  PubMed  Google Scholar 

  6. Nakamura Y, Yashiro M, Uehara R, Oki I, Kayaba K, Yanagawa H. Increasing incidence of Kawasaki disease in Japan: nationwide survey. Pediatr Int. 2008;50:287–90.

    Article  PubMed  Google Scholar 

  7. Liang CD, Kuo HC, Yang KD, Wang CL, Ko SF. Coronary artery fistula associated with Kawasaki disease. Am Heart J. 2009;157:584–8.

    Article  PubMed  Google Scholar 

  8. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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. 2004;114:1708–33.

    Article  PubMed  Google Scholar 

  9. Soylemezoglu O, Peru H, Gonen S, Cetinyurek A, Ozkaya O, Bakkaloglu S, et al. CTLA-4 +49 A/G genotype and HLA-DRB1 polymorphisms in Turkish patients with Henoch-Schonlein purpura. Pediatr Nephrol. 2008;23:1239–44.

    Article  PubMed  Google Scholar 

  10. Yang KD, Liu CA, Chang JC, Chuang H, Ou CY, Hsu TY, et al. Polymorphism of the immune-braking gene CTLA-4 (+49) involved in gender discrepancy of serum total IgE levels and allergic diseases. Clin Exp Allergy. 2004;34:32–7.

    Article  PubMed  CAS  Google Scholar 

  11. Chang JC, Liu CA, Chuang H, Ou CY, Hsu TY, Huang EY, et al. Gender-limited association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphism with cord blood IgE levels. Pediatr Allergy Immunol. 2004;15:506–12.

    Article  PubMed  Google Scholar 

  12. Momin S, Flores S, Angel BB, Codner DE, Carrasco PE, Perez-Bravo F. Interactions between programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) gene polymorphisms in type 1 diabetes. Diabetes Res Clin Pract. 2009;83:289–94.

    Article  PubMed  CAS  Google Scholar 

  13. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423:506–11.

    Article  PubMed  CAS  Google Scholar 

  14. Kristiansen OP, Larsen ZM, Pociot F. CTLA-4 in autoimmune diseases—a general susceptibility gene to autoimmunity? Genes Immun. 2000;1:170–84.

    Article  PubMed  CAS  Google Scholar 

  15. Munthe-Kaas MC, Carlsen KH, Helms PJ, Gerritsen J, Whyte M, Feijen M, et al. CTLA-4 polymorphisms in allergy and asthma and the TH1/TH2 paradigm. J Allergy Clin Immunol. 2004;114:280–7.

    Article  PubMed  CAS  Google Scholar 

  16. Kuo HC, Wang CL, Liang CD, Yu HR, Chen HH, Wang L, et al. Persistent monocytosis after intravenous immunoglobulin therapy correlated with the development of coronary artery lesions in patients with Kawasaki disease. J Microbiol Immunol Infect. 2007;40:395–400.

    PubMed  Google Scholar 

  17. Kuo HC, Yang KD, Liang CD, Bong CN, Yu HR, Wang L, et al. The relationship of eosinophilia to intravenous immunoglobulin treatment failure in Kawasaki disease. Pediatr Allergy Immunol. 2007;18:354–9.

    Article  PubMed  Google Scholar 

  18. Kuo HC, Wang CL, Liang CD, Yu HR, Huang CF, Wang L, et al. Association of lower eosinophil-related T helper 2 (Th2) cytokines with coronary artery lesions in Kawasaki disease. Pediatr Allergy Immunol. 2009;20:266–72.

    Article  PubMed  Google Scholar 

  19. Akagi T, Rose V, Benson LN, Newman A, Freedom RM. Outcome of coronary artery aneurysms after Kawasaki disease. J Pediatr. 1992;121:689–94.

    Article  PubMed  CAS  Google Scholar 

  20. Shulman ST, De Inocencio J, Hirsch R. Kawasaki disease. Pediatr Clin North Am. 1995;42:1205–22.

    PubMed  CAS  Google Scholar 

  21. Yang KD, Ou CY, Chang JC, Chen RF, Liu CA, Liang HM, et al. Infant frequent wheezing correlated to Clara cell protein 10 (CC10) polymorphism and concentration, but not allergy sensitization, in a perinatal cohort study. J Allergy Clin Immunol. 2007;120:842–8.

    Article  PubMed  CAS  Google Scholar 

  22. Hirao J, Hibi S, Andoh T, Ichimura T. High levels of circulating interleukin-4 and interleukin-10 in Kawasaki disease. Int Arch Allergy Immunol. 1997;112:152–6.

    Article  PubMed  CAS  Google Scholar 

  23. Furukawa S, Matsubara T, Motohashi T, Sasai K, Nakachi S, Umezawa Y, et al. Increased expression of Fc epsilon R2/CD23 on peripheral blood B lymphocytes and serum IgE levels in Kawasaki disease. Int Arch Allergy Appl Immunol. 1991;95:7–12.

    Article  PubMed  CAS  Google Scholar 

  24. Furuno K, Yuge T, Kusuhara K, Takada H, Nishio H, Khajoee V, et al. CD25+CD4+ regulatory T cells in patients with Kawasaki disease. J Pediatr. 2004;145:385–90.

    Article  PubMed  CAS  Google Scholar 

  25. Matsubara T, Anwar R, Fujiwara M, Ichiyama T, Furukawa S. CTLA-4 (CD152) expression in peripheral blood T cells in Kawasaki disease. Clin Exp Immunol. 2003;132:169–73.

    Article  PubMed  CAS  Google Scholar 

  26. Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ. CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease. J Immunol. 2001;165:6606–11.

    Google Scholar 

  27. Maurer M, Loserth S, Kolb-Maurer A, Ponath A, Wiese S, Kruse N, et al. A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics. 2002;54:1–8.

    Article  PubMed  Google Scholar 

  28. Ahmed S, Ihara K, Kanemitsu S, Nakashima H, Otsuka T, Tsuzaka K, et al. Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population. Rheumatology (Oxford). 2001;40:662–7.

    Article  CAS  Google Scholar 

  29. Lee YJ, Huang FY, Lo FS, Wang WC, Hsu CH, Kao HA, et al. Association of CTLA4 gene A-G polymorphism with type 1 diabetes in Chinese children. Clin Endocrinol (Oxford). 2000;52:153–7.

    Article  CAS  Google Scholar 

  30. Onouchi Y, Gunji T, Burns JC, Shimizu C, Newburger JW, Yashiro M, et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet. 2008;40:35–42.

    Article  PubMed  CAS  Google Scholar 

  31. Burgner D, Davila S, Breunis WB, Ng SB, Li Y, Bonnard C, et al. A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet. 2009;5:e1000319.

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was in part supported by funding from grant NSC 97-2314-B-182A-054-MY2 and NSC 98-2314-B-182A-004-MY3 from the National Science Council of Taiwan and grant CMRPG880251 from the Chang Gung Memorial Hospital, Taiwan; and funding from Excellence for Cancer Research Center Grant (DOH99-TD-C-111-002) through the funding by Department of Health, Executive Yuan, Taiwan. This work was carried out as a cooperative project of the institutes of all authors. The institutes had no influence on the collection, analysis, and interpretation of the data, and on the preparation of the manuscript.

Competing interests

The authors have declared that no competing interests exist.

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Authors and Affiliations

  1. Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan

    Ho-Chang Kuo, Hong-Ren Yu, Chieh-An Liu & Kuender D. Yang

  2. Graduate Institute of Clinical Medical Science, Chang Gung University, Kaohsiung, Taiwan

    Ho-Chang Kuo, Hong-Ren Yu, I-Chun Lin & Kuender D. Yang

  3. Division of Cardiology, Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan

    Chi-Di Liang

  4. Po-Jen Hospital, Kaohsiung, Taiwan

    Chih-Lu Wang

  5. Clinical Genomic & Proteomic Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital Kaohsiung Medical Center, Kaohsiung, Taiwan

    Jen-Chieh Chang & Chiu-Ping Lee

  6. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Jen-Chieh Chang

  7. Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Wei-Chiao Chang

  8. Department of Medical Research and Pediatric Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, 123 Ta-Pei Road, Niaosung Hsiang, Kaohsiung, Taiwan

    Kuender D. Yang

  9. Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Wei-Chiao Chang

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  1. Ho-Chang Kuo
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  2. Chi-Di Liang
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  8. Chiu-Ping Lee
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  9. Wei-Chiao Chang
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  10. Kuender D. Yang
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Correspondence to Kuender D. Yang.

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Kuo, HC., Liang, CD., Yu, HR. et al. CTLA-4, Position 49 A/G Polymorphism Associated with Coronary Artery Lesions in Kawasaki Disease. J Clin Immunol 31, 240–244 (2011). https://doi.org/10.1007/s10875-010-9484-4

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  • DOI: https://doi.org/10.1007/s10875-010-9484-4

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