Abstract 38: Variations in ORAI1 gene associated with Kawasaki disease

• Published in: Circulation (New York, N.Y.) N.Y.), 2015-04, Vol.131 (suppl_2)
• Main Authors: Onouchi, Yoshihiro, Fukazawa, Ryuji, Yamamura, Kenichiro, Suzuki, Hiroyuki, Suenaga, Tomohiro, Takeuchi, Takashi, Yoshikawa, Norishige, Hamada, Hiromichi, Honda, Takafumi, Yasukawa, Kumi, Terai, Masaru, Ebata, Ryota, Higashi, Kouji, Saji, Tsutomu, Kemmotsu, Yasushi, Takatsuki, Shinichi, Ouchi, Kazunobu, Kishi, Fumio, Yoshikawa, Tetsushi, Nagai, Toshiro, Hamamoto, Kunihiro, Sato, Yoshitake, Honda, Akihito, Kobayashi, Hironobu, Sato, Junichi, Shibuta, Shoichi, Miyawaki, Masakazu, Oishi, Ko, Yamaga, Hironobu, Aoyagi, Noriyuki, Iwahashi, Seiji, Murata, Yuji, Fujino, Akihiro, Ozaki, Kouichi, Kawasaki, Tomisaku, Abe, Jun, Seki, Mitsuru, Kobayashi, Tohru, Arakawa, Kouichi, Ogawa, Shunichi, Hara, Toshiro, Hata, Akira, Tanaka, Toshihiro
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.131.suppl_2.38

Abstract only Kawasaki disease (KD; MIM611775) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD have suggested up-regulation of Ca2+/NFAT pathway as one of the main pathophysiological processes in KD. In this study, we focused on ORAI1, a gene for a channel involved in store operated Ca2+ entry located on 12q24 where positive linkage signal was seen in our previous sib pair study of KD, and conducted a genetic association study. By re-sequencing 17.4kb of ORAI1 region for 94 subjects, we identified 37 variants with minor allele frequencies larger than 0.05. After selecting 9 tagging SNPs which represent 37 variants we performed an association study using 730 KD cases and 1315 controls. As a result, one tagging SNP located within exon2 showed nominal association (rs3741596; OR = 1.19, 95%CI 1.02~1.40, P = 0.028). The same trend of association was observed in an independent case control panel (1813 KD cases and 1097 controls, OR=1.22, 95% CI 1.06-1.40, P = 0.0056) and a significant P value was observed in a meta-analysis (OR = 1.21, 95%CI 1.09~1.34, P = 0.00041). Furthermore, we also found a rare 6 base-pair insertion polymorphism which cause elongation of proline repeat within N-terminal cytoplasmic domain of the ORAI1 protein was overrepresented in KD cases (rs78448924; OR = 3.91, 95%CI 1.30~11.80, P=0.010). These data indicate altered ORAI1 function confers susceptibility of KD and further highlight importance of the Ca2+/NFAT pathway in the disease pathogenesis.