PLoS ONE (Jan 2016)

Variations in ORAI1 Gene Associated with Kawasaki Disease.

  • Yoshihiro Onouchi,
  • Ryuji Fukazawa,
  • Kenichiro Yamamura,
  • Hiroyuki Suzuki,
  • Nobuyuki Kakimoto,
  • Tomohiro Suenaga,
  • Takashi Takeuchi,
  • Hiromichi Hamada,
  • Takafumi Honda,
  • Kumi Yasukawa,
  • Masaru Terai,
  • Ryota Ebata,
  • Kouji Higashi,
  • Tsutomu Saji,
  • Yasushi Kemmotsu,
  • Shinichi Takatsuki,
  • Kazunobu Ouchi,
  • Fumio Kishi,
  • Tetsushi Yoshikawa,
  • Toshiro Nagai,
  • Kunihiro Hamamoto,
  • Yoshitake Sato,
  • Akihito Honda,
  • Hironobu Kobayashi,
  • Junichi Sato,
  • Shoichi Shibuta,
  • Masakazu Miyawaki,
  • Ko Oishi,
  • Hironobu Yamaga,
  • Noriyuki Aoyagi,
  • Megumi Yoshiyama,
  • Ritsuko Miyashita,
  • Yuji Murata,
  • Akihiro Fujino,
  • Kouichi Ozaki,
  • Tomisaku Kawasaki,
  • Jun Abe,
  • Mitsuru Seki,
  • Tohru Kobayashi,
  • Hirokazu Arakawa,
  • Shunichi Ogawa,
  • Toshiro Hara,
  • Akira Hata,
  • Toshihiro Tanaka

DOI
https://doi.org/10.1371/journal.pone.0145486
Journal volume & issue
Vol. 11, no. 1
p. e0145486

Abstract

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Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.