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 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.

Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities

“…16 Importantly, polymorphisms in 3 calcium pathway genes, ITPKC, ORAI1, and SLC8A1, have now been validated to be associated with KD susceptibility and aneurysm formation. 17,18 The ITPKC rs28493229 was excluded from the pathway analysis to avoid false-positive results because of the strong association of ITPKC with KD. We were unable to confirm an association with the ORAI1 rs3741596 reported in Japanese cohorts because of the low (<1%) risk allele frequency of the ORAI1 SNP in individuals of European and Hispanic descent.…”

Evaluation of Epidemiological and Clinical Properties of Kawasaki Disease: A Single Center Experience

“…Tsukahara et al (19) demonstrated that methylenetetrahydrofolate reductase gene polymorphism has an effect on the development of a coronary artery aneurysm. Onouchi et al (20) reported that the frequen- cy of the allele of rs3741596 in ORAI1 gene is >20 times higher in Japanese compared with Europeans and alterations have an association with KD. For this reason, more studies are required to explain the probable genetic predisposition in different ethnicities.…”

The genetics of Kawasaki disease

“…40 However, from its still high cost, GWAS for such low-frequency variants requiring whole-exome sequencing (WES) or whole-genome sequencing (WGS) has not become widely available. Therefore, at this moment, as coincidence of rare and common susceptible variants in the same genes experienced for ORAI1 15 and TLR6 17 is suggesting, target resequencing of a susceptibility gene panel might be a cost-effective way to identify novel rare susceptibility variants. Genome-wide searches by WES or WGS would be more successful when cases with extreme phenotypes are the targets.…”

“…12 In the subsequent case-control association studies, inositol 1,4,5-trisphosphate 3-kinase C (ITPKC), 13 caspase-3 (CASP3) 14 and calcium release-activated calcium modulator 1 (ORAI1) 15 genes located within the candidate regions were identified as susceptibility genes for KD. Another genome-wide linkage study using SNPs as genetic markers identified five chromosomal regions with suggestive evidence of linkage (LOD score > 3.0).…”

“…19,[21][22][23][24] In the case of ORAI1 gene, a common SNP associated with KD in the Japanese is almost monomorphic in Europeans. 15 Thus it has become clear that genetic factors of KD susceptibility are heterogeneous in their constituents and their effect sizes among ethnicities. Given that interaction between genetic and environmental factors determines the complex human traits, it is not unusual that in populations exposed to different environments and having different traditions and cultures which influence their lifestyles, different genetic factors are associated with the disease.…”