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ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Nature Genetics volume 40, pages 35–42 (2008)Cite this article

Abstract

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.

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Figure 1: Results of SNP screening of chromosome 19 and structure of the linkage disequilibrium (LD) block in Japanese individuals showing SNPs significantly associated with Kawasaki disease.
Figure 2: Comparison of relative mRNA expression of ITPKC in different tissues and cell lines.
Figure 3: Allele-specific transcript quantification of ITPKC in PBMC.
Figure 4: Negative regulatory role of ITPKC expression in stimulated Jurkat cells.
Figure 5: Reduced splicing efficiency of intron 1 and reduced ITPKC transcript abundance mediated by the itpkc_3 C allele.

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Acknowledgements

We thank the individuals with Kawasaki disease and their families who participated in this project. We are grateful to H. Aotsuka, H. Nakajima, F. Kudo, M. Miura, K. Akagi, T. Matsubara, M. Nishibatake, S. Oku, K. Sameshima, Y. Tanaka, Y. Nomura, S. Ogita, M. Sakauchi, T. Isobe, T. Sano, T. Matsushita and other physicians who contributed DNA samples. We thank J. Pancheri and A. Baker for collection of DNA samples and D. Scherrer, H. Sugiyama and M. Saito for technical assistance. This work was supported by grants from the Japanese Millennium Project, from the Japan Society for the Promotion of Science (16591069 to Y.O.) and from the National Heart, Lung, Blood Institute of the National Institutes of Health (HL69413 to J.C.B.).

Author information

Author notes

  1. Yoichi Kaburagi

    Present address: Present address: Department of Pediatrics, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa 245-8575, Japan.,

Authors and Affiliations

  1. Laboratory for Gastrointestinal Diseases, SNP Research Center, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Yoshihiro Onouchi, Tomohiko Gunji & Akira Hata

  2. Department of Hard Tissue Engineering, Graduate School Tokyo Medical and Dental University, Tokyo, 113-8549, Japan

    Tomohiko Gunji

  3. Department of Pediatrics, University of California San Diego, School of Medicine, La Jolla, California

    Jane C Burns & Chisato Shimizu

  4. Rady Children's Hospital, San Diego, 92093, California, USA

    Jane C Burns & Chisato Shimizu

  5. Department of Cardiology, Boston Children's Hospital, Boston, 02115, Massachusetts, USA

    Jane W Newburger

  6. Department of Public Health, Jichi Medical School, Minamikawachi, 329-0498, Tochigi, Japan

    Mayumi Yashiro & Yoshikazu Nakamura

  7. Saitama Prefectural University, Koshigaya, 343-8540, Saitama, Japan

    Hiroshi Yanagawa

  8. Department of Preventive Medicine, Shinshu University School of Medicine, 390-8621, Matsumoto, Japan

    Keiko Wakui & Yoshimitsu Fukushima

  9. Department of Molecular Genetics, Kawasaki Medical School, Kurashiki, 701-0192, Okayama, Japan

    Fumio Kishi

  10. Department of Pediatrics, Fukuoka University School of Medicine, Fukuoka, 831-8501, Fukuoka, Japan

    Kunihiro Hamamoto

  11. Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, 276-8524, Chiba, Japan

    Masaru Terai

  12. Department of Pediatrics, Fuji Heavy Industries Ltd. Health Insurance Society General Ohta Hospital, Ohta, 373-8585, Gunma, Japan

    Yoshitake Sato

  13. Department of Pediatrics, Kawasaki Medical School, Kurashiki, 701-0192, Okayama, Japan

    Kazunobu Ouchi

  14. Department of Pediatrics, Toho University School of Medicine, Tokyo, 143-8541, Japan

    Tsutomu Saji

  15. Department of Pediatrics, Yokohama Minami Kyousai Hospital, Yokohama, 236-0037, Kanagawa, Japan

    Akiyoshi Nariai & Yoichi Kaburagi

  16. Department of Pediatrics, Fujita Health University, Toyoake, 470-1192, Aichi, Japan

    Tetsushi Yoshikawa

  17. Department of Pediatrics, Toyokawa Citizen's Hospital, Toyokawa, 442-8561, Aichi, Japan

    Kyoko Suzuki

  18. Department of Pediatrics, National Hospital Organization Kure Medical Center, Kure, 737-0023, Okayama, Japan

    Takeo Tanaka

  19. Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya, 343-8555, Saitama, Japan

    Toshiro Nagai

  20. Department of Pediatrics, Kawasaki Municipal Hospital, Kawasaki, 210-0013, Japan

    Hideo Cho

  21. Department of Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Akihiro Fujino

  22. Laboratory for Genotyping, SNP Research Center, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Akihiro Sekine

  23. Laboratory for Medical Informatics, SNP Research Center, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Reiichiro Nakamichi & Tatsuhiko Tsunoda

  24. Japan Kawasaki Disease Research Center, Tokyo, 111-0031, Japan

    Tomisaku Kawasaki

  25. Laboratory for Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

    Yusuke Nakamura

  26. SNP Research Center, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Yusuke Nakamura

Authors
  1. Yoshihiro Onouchi
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  2. Tomohiko Gunji
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Contributions

Y.O., A.H. and Yusuke N. designed the study. Y.O., J.C.B., C.S., J.W.N., F.K., K.H., M.T., Y.S., K.O., T.S., A.N., Y.K., T.Y., K.S., Takeo T., T.N., H.C. and A.F. collected most of the samples. M.Y., Yoshikazu N., H.Y. and T.K. provided information regarding the Japanese nation-wide survey of Kawasaki disease. K.W. and Y.F. established lymphoblastoid cell lines of individuals with Kawasaki disease. Tatsuhiko T. and A.S. supported the initial SNP screening by providing genotyping data for the control population. Y.O. performed genotyping and statistical analyses. R.N. and Tatsuhiko T. performed logistic regression analyses. Y.O. and T.G. performed functional assays. Y.O., J.C.B., C.S., J.W.N. and A.H. wrote the paper.

Corresponding author

Correspondence to Yoshihiro Onouchi.

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Onouchi, Y., Gunji, T., Burns, J. et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet 40, 35–42 (2008). https://doi.org/10.1038/ng.2007.59

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