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

Yoshihiro Onouchi, Tomohiko Gunji, Jane C. Burns, Chisato Shimizu, Jane W. Newburger, Mayumi Yashiro, Yoshikazu Nakamura, Hiroshi Yanagawa, Keiko Wakui, Yoshimitsu Fukushima, Fumio Kishi, Kunihiro Hamamoto, Masaru Terai, Yoshitake Sato, Kazunobu Ouchi, Tsutomu Saji, Akiyoshi Nariai, Yoichi Kaburagi, Tetsushi Yoshikawa, Kyoko SuzukiTakeo Tanaka, Toshiro Nagai, Hideo Cho, Akihiro Fujino, Akihiro Sekine, Reiichiro Nakamichi, Tatsuhiko Tsunoda, Tomisaku Kawasaki, Yusuke Nakamura, Akira Hata

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308 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)35-42
Number of pages8
JournalNature Genetics
Volume40
Issue number1
DOIs
Publication statusPublished - 01-2008

All Science Journal Classification (ASJC) codes

  • Genetics

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    Onouchi, Y., Gunji, T., Burns, J. C., Shimizu, C., Newburger, J. W., Yashiro, M., Nakamura, Y., Yanagawa, H., Wakui, K., Fukushima, Y., Kishi, F., Hamamoto, K., Terai, M., Sato, Y., Ouchi, K., Saji, T., Nariai, A., Kaburagi, Y., Yoshikawa, T., ... Hata, A. (2008). ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nature Genetics, 40(1), 35-42. https://doi.org/10.1038/ng.2007.59