Article abstract
Nature Genetics 40, 35 - 42 (2008)
Published online: 16 December 2007 | doi:10.1038/ng.2007.59
ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms
Yoshihiro Onouchi1, Tomohiko Gunji1,2, Jane C Burns3, Chisato Shimizu3, Jane W Newburger4, Mayumi Yashiro5, Yoshikazu Nakamura5, Hiroshi Yanagawa6, Keiko Wakui7, Yoshimitsu Fukushima7, Fumio Kishi8, Kunihiro Hamamoto9, Masaru Terai10, Yoshitake Sato11, Kazunobu Ouchi12, Tsutomu Saji13, Akiyoshi Nariai14, Yoichi Kaburagi14,26, Tetsushi Yoshikawa15, Kyoko Suzuki16, Takeo Tanaka17, Toshiro Nagai18, Hideo Cho19, Akihiro Fujino20, Akihiro Sekine21, Reiichiro Nakamichi22, Tatsuhiko Tsunoda22, Tomisaku Kawasaki23, Yusuke Nakamura24,25 & Akira Hata1
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.
- Laboratory for Gastrointestinal Diseases, SNP Research Center, RIKEN, Yokohama, Kanagawa, 230-0045, Japan.
- Department of Hard Tissue Engineering, Graduate School Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
- Department of Pediatrics, University of California San Diego, School of Medicine, La Jolla, California and Rady Children's Hospital San Diego, California 92093, USA.
- Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
- Department of Public Health, Jichi Medical School, Minamikawachi, Tochigi 329-0498, Japan.
- Saitama Prefectural University, Koshigaya, Saitama 343-8540, Japan.
- Department of Preventive Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
- Department of Molecular Genetics, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan.
- Department of Pediatrics, Fukuoka University School of Medicine, Fukuoka, Fukuoka 831-8501, Japan.
- Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Chiba 276-8524, Japan.
- Department of Pediatrics, Fuji Heavy Industries Ltd. Health Insurance Society General Ohta Hospital, Ohta, Gunma 373-8585, Japan.
- Department of Pediatrics, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan.
- Department of Pediatrics, Toho University School of Medicine, Tokyo 143-8541, Japan.
- Department of Pediatrics, Yokohama Minami Kyousai Hospital, Yokohama, 236-0037, Kanagawa, Japan.
- Department of Pediatrics, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
- Department of Pediatrics, Toyokawa Citizen's Hospital, Toyokawa, Aichi 442-8561, Japan.
- Department of Pediatrics, National Hospital Organization Kure Medical Center, Kure, Okayama 737-0023, Japan.
- Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya, Saitama 343-8555, Japan.
- Department of Pediatrics, Kawasaki Municipal Hospital, Kawasaki 210-0013, Japan.
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
- Laboratory for Genotyping, SNP Research Center, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
- Laboratory for Medical Informatics, SNP Research Center, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
- Japan Kawasaki Disease Research Center, Tokyo 111-0031, Japan.
- Laboratory for Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
- SNP Research Center, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
- Present address: Department of Pediatrics, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa 245-8575, Japan.
Correspondence to: Yoshihiro Onouchi1 e-mail: onouchi@src.riken.jp
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