Variations in ORAI1 Gene Associated with Kawasaki Disease

• DOI: 10.1371/journal.pone.0145486
• Publication Date: 2016-01-20T20:52:05Z
• Authors: 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
• Keywords: Male; Adolescent; ORAI1 Protein; Science; Mucocutaneous Lymph Node Syndrome; Polymorphism, Single Nucleotide; White People; Young Adult; 03 medical and health sciences; Asian People; Gene Frequency; Japan; Humans; Genetic Predisposition to Disease; 0303 health sciences; Chromosomes, Human, Pair 12; Siblings; Q; R; 3. Good health; Mutagenesis, Insertional; Medicine; Calcium; Female; Calcium Channels; Research Article

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.