Onouchi Yoshihiro, Gunji Tomohiko, Burns Jane C, Shimizu Chisato, Newburger Jane W, Yashiro Mayumi, Nakamura Yoshikazu, Yanagawa Hiroshi, Wakui Keiko, Fukushima Yoshimitsu, Kishi Fumio, Hamamoto Kunihiro, Terai Masaru, Sato Yoshitake, Ouchi Kazunobu, Saji Tsutomu, Nariai Akiyoshi, Kaburagi Yoichi, Yoshikawa Tetsushi, Suzuki Kyoko, Tanaka Takeo, Nagai Toshiro, Cho Hideo, Fujino Akihiro, Sekine Akihiro, Nakamichi Reiichiro, Tsunoda Tatsuhiko, Kawasaki Tomisaku, Nakamura Yusuke, Hata Akira
Laboratory for Gastrointestinal Diseases, SNP Research Center, RIKEN, Yokohama, Kanagawa, 230-0045, Japan.
Nat Genet. 2008 Jan;40(1):35-42. doi: 10.1038/ng.2007.59. Epub 2007 Dec 16.
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.
川崎病是一种病因不明的儿童系统性血管炎，怀疑有遗传影响。我们在19号染色体q13.2上的肌醇1,4,5 -三磷酸3 -激酶C（ITPKC）基因中鉴定出一个功能性单核苷酸多态性（itpkc_3），它与川崎病易感性显著相关，并且在日本和美国儿童中都与冠状动脉病变风险增加有关。转染实验表明，itpkc_3的C等位基因降低了ITPKC mRNA的剪接效率。ITPKC通过Ca2+/NFAT信号通路作为T细胞活化的负调节因子，C等位基因可能导致川崎病中的免疫高反应性。这一发现为川崎病免疫激活机制提供了新见解，并强调了活化T细胞在这种血管炎发病机制中的重要性。
