Abstract 38: Variations in ORAI1 gene associated with Kawasaki disease
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.
Author Disclosures: Y. Onouchi: None. R. Fukazawa: None. K. Yamamura: None. H. Suzuki: None. T. Suenaga: None. T. Takeuchi: None. N. Yoshikawa: None. H. Hamada: None. T. Honda: None. K. Yasukawa: None. M. Terai: None. R. Ebata: None. K. Higashi: None. T. Saji: None. Y. Kemmotsu: None. S. Takatsuki: None. K. Ouchi: None. F. Kishi: None. T. Yoshikawa: None. T. Nagai: None. K. Hamamoto: None. Y. Sato: None. A. Honda: None. H. Kobayashi: None. J. Sato: None. S. Shibuta: None. M. Miyawaki: None. K. Oishi: None. H. Yamaga: None. N. Aoyagi: None. S. Iwahashi: None. Y. Murata: None. A. Fujino: None. K. Ozaki: None. T. Kawasaki: None. J. Abe: None. M. Seki: None. T. Kobayashi: 4. Speakers’ Bureau; Modest; Teijin Pharma. 5. Honoraria; Modest; Teijin Pharma. K. Arakawa: None. S. Ogawa: None. T. Hara: None. A. Hata: None. T. Tanaka: None.
- © 2015 by American Heart Association, Inc.