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

Research output: Contribution to journalArticle

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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 - 01-01-2008

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Inositol 1,4,5-trisphosphate 3-kinase
Coronary Aneurysm
Mucocutaneous Lymph Node Syndrome
Disease Susceptibility
Coronary Vessels
Alleles
T-Lymphocytes
Systemic Vasculitis
Vasculitis
Single Nucleotide Polymorphism
Transfection
Chromosomes
Pediatrics
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Onouchi, Y., Gunji, T., Burns, J. C., Shimizu, C., Newburger, J. W., Yashiro, M., ... 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
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. / ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. In: Nature Genetics. 2008 ; Vol. 40, No. 1. pp. 35-42.
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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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Onouchi, Y, Gunji, T, Burns, JC, Shimizu, C, Newburger, JW, 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, Suzuki, K, Tanaka, T, Nagai, T, Cho, H, Fujino, A, Sekine, A, Nakamichi, R, Tsunoda, T, Kawasaki, T, Nakamura, Y & Hata, A 2008, 'ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms', Nature Genetics, vol. 40, no. 1, pp. 35-42. https://doi.org/10.1038/ng.2007.59

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

In: Nature Genetics, Vol. 40, No. 1, 01.01.2008, p. 35-42.

Research output: Contribution to journalArticle

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AU - Onouchi, Yoshihiro

AU - Gunji, Tomohiko

AU - Burns, Jane C.

AU - Shimizu, Chisato

AU - Newburger, Jane W.

AU - Yashiro, Mayumi

AU - Nakamura, Yoshikazu

AU - Yanagawa, Hiroshi

AU - Wakui, Keiko

AU - Fukushima, Yoshimitsu

AU - Kishi, Fumio

AU - Hamamoto, Kunihiro

AU - Terai, Masaru

AU - Sato, Yoshitake

AU - Ouchi, Kazunobu

AU - Saji, Tsutomu

AU - Nariai, Akiyoshi

AU - Kaburagi, Yoichi

AU - Yoshikawa, Tetsushi

AU - Suzuki, Kyoko

AU - Tanaka, Takeo

AU - Nagai, Toshiro

AU - Cho, Hideo

AU - Fujino, Akihiro

AU - Sekine, Akihiro

AU - Nakamichi, Reiichiro

AU - Tsunoda, Tatsuhiko

AU - Kawasaki, Tomisaku

AU - Nakamura, Yusuke

AU - Hata, Akira

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