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 Ca2+/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca2+ release activated Ca2+ (CRAC) channel mediating store-operated Ca2+ 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 Ca2+/NFAT pathway in the pathogenesis of this disorder.
Highlights
Kawasaki disease (KD; MIM #611775) is an acute febrile illness which predominantly affects infants and children younger than 5 years of age [1;2]
Intravenous immunoglobulin (IVIG) therapy has proven to be effective in preventing coronary artery lesions (CALs) [4]; 10–15% of patients poorly respond to the treatment and are at high risk for developing CALs
We focused on ORAI1, a Ca2+ release activated Ca2+ (CRAC) channel that plays a key role in the store-operated Ca2+ entry (SOCE) mechanism on which various immune cells rely for activation of the Ca2+/nuclear factor of activated T-cells (NFAT) pathway
Summary
Kawasaki disease (KD; MIM #611775) is an acute febrile illness which predominantly affects infants and children younger than 5 years of age [1;2]. Intravenous immunoglobulin (IVIG) therapy has proven to be effective in preventing coronary artery lesions (CALs) [4]; 10–15% of patients poorly respond to the treatment and are at high risk for developing CALs. Currently, KD is a leading cause of acquired heart diseases in children in developed countries. After more than 40 years since Kawasaki first described the disease [1], the etiology still remains unknown. A higher prevalence in children of Asian ancestry [5;6] and evidence of familial aggregation of the disease [7;8] have strongly indicated an involvement of genetic susceptibility. The identification of genetic factors contributing to the inter-ethnic and inter-individual difference in susceptibility to KD will help to clarify disease etiology
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
