title: Variations in ORAI1 Gene Associated with Kawasaki Disease.
abstract: 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.
authors.affiliation: Laboratory for Cardiovascular Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.|Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Onouchi
authors.affiliation: Department of Pediatrics, Nippon Medical School, Tokyo, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukazawa
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Hiroyuki
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authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Nobuyuki
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authors.lastname: Kakimoto
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Tomohiro
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authors.lastname: Suenaga
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Takashi
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authors.lastname: Takeuchi
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Hiromichi
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authors.lastname: Hamada
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Takafumi
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authors.lastname: Honda
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Kumi
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authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Masaru
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authors.lastname: Terai
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Ryota
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authors.affiliation: Department of Cardiology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Kouji
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authors.lastname: Higashi
authors.affiliation: Department of Pediatrics, Toho University Medical Center, Omori Hospital, Tokyo, Japan.
authors.forename: Tsutomu
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authors.affiliation: Department of Pediatrics, Toho University Medical Center, Omori Hospital, Tokyo, Japan.
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authors.affiliation: Department of Pediatrics, Toho University Medical Center, Omori Hospital, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takatsuki
authors.affiliation: Department of Pediatrics, Kawasaki Medical School, Kurashiki, Japan.
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authors.affiliation: Department of Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan.
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authors.affiliation: Department of Pediatrics, Fujita Health University, Toyoake, Japan.
authors.forename: Tetsushi
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authors.affiliation: Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan.
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authors.affiliation: Department of Occupational Therapy, International University of Health and Welfare, Okawa, Japan.
authors.forename: Kunihiro
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authors.affiliation: Department of Pediatrics, Fuji Heavy Industry Health Insurance Society Ota Memorial Hospital, Ota, Japan.
authors.forename: Yoshitake
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authors.lastname: Sato
authors.affiliation: Department of Pediatrics, Asahi General Hospital, Asahi, Japan.
authors.forename: Akihito
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authors.affiliation: Department of Pediatrics, Asahi General Hospital, Asahi, Japan.
authors.forename: Hironobu
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authors.affiliation: Department of Pediatrics, Funabashi Municipal Medical Center, Funabashi, Japan.
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authors.affiliation: Department of Pediatrics, Kinan Hospital, Tanabe, Japan.
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authors.affiliation: Department of Pediatrics, Hashimoto Municipal Hospital, Hashimoto, Japan.
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authors.affiliation: Department of Pediatrics, Wakayama Rosai Hospital, Wakayama, Japan.
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authors.affiliation: Department of Pediatrics, Hidaka General Hospital, Gobo, Japan.
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authors.affiliation: Department of Pediatrics, Izumiotsu Municipal Hospital, Izumiotsu, Japan.
authors.forename: Ritsuko
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authors.affiliation: Department of Pediatrics, Sendai City Hospital, Sendai, Japan.
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authors.lastname: Murata
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authors.affiliation: Laboratory for Cardiovascular Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
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authors.affiliation: Japan Kawasaki Disease Research Center, Tokyo, Japan.
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authors.lastname: Kawasaki
authors.affiliation: Department of Allergy & Immunology, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Jun
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authors.affiliation: Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.
authors.forename: Mitsuru
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authors.affiliation: Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Tohru
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authors.affiliation: Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.
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authors.affiliation: Department of Pediatrics, Nippon Medical School, Tokyo, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hata
authors.affiliation: Laboratory for Cardiovascular Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.|Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000293:Adolescent; D044466:Asian People / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000235:genetics* / Q000473:pathology; D016254:Mutagenesis, Insertional; D000071740:ORAI1 Protein; D020641:Polymorphism, Single Nucleotide; D035781:Siblings; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D015220:Calcium Channels; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D002118:Calcium