ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms.
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.
Onouchi
Yoshihiro
Y
Laboratory for Gastrointestinal Diseases, SNP Research Center, RIKEN, Yokohama, Kanagawa, 230-0045, Japan. onouchi@src.riken.jp
Gunji
Tomohiko
T
Burns
Jane C
JC
Shimizu
Chisato
C
Newburger
Jane W
JW
Yashiro
Mayumi
M
Nakamura
Yoshikazu
Y
Yanagawa
Hiroshi
H
Wakui
Keiko
K
Fukushima
Yoshimitsu
Y
Kishi
Fumio
F
Hamamoto
Kunihiro
K
Terai
Masaru
M
Sato
Yoshitake
Y
Ouchi
Kazunobu
K
Saji
Tsutomu
T
Nariai
Akiyoshi
A
Kaburagi
Yoichi
Y
Yoshikawa
Tetsushi
T
Suzuki
Kyoko
K
Tanaka
Takeo
T
Nagai
Toshiro
T
Cho
Hideo
H
Fujino
Akihiro
A
Sekine
Akihiro
A
Nakamichi
Reiichiro
R
Tsunoda
Tatsuhiko
T
Kawasaki
Tomisaku
T
Nakamura
Yusuke
Y
Hata
Akira
A
D044466:Asian People / Q000235:genetics; D002888:Chromosomes, Human, Pair 19; D003323:Coronary Aneurysm / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008213:Lymphocyte Activation; D009080:Mucocutaneous Lymph Node Syndrome / Q000235:genetics* / Q000276:immunology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D013601:T-Lymphocytes / Q000276:immunology
D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase