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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.

BackgroundTo clarify the contribution of patient age to the development of coronary artery lesions (CALs) associated with Kawasaki disease (KD), epidemiologic features and prognostic factors were investigated using hospital-based complete enumeration surveys in a specific area.MethodsConsecutive KD cases identified between October 1999 and September 2012 in Wakayama Prefecture, Japan, were analyzed. The primary outcome measure was the presence/absence of CALs (giant aneurysm, mid- or small-sized aneurysm, and dilatation) on echocardiography 1 month after disease onset. Demographics and medical treatment factors were compared between the patients with and without CALs. Odds ratios (ORs) and 95% confidence intervals (CIs) of explanatory variables (age, gender, and factors related to high-dose intravenous immunoglobulin treatment) for the development of CALs were determined.ResultsThe median age of the 1415 patients (796 males, 619 females) was 25 months after excluding 2 children of foreign residents; 2.2% of the patients had a past history of KD, and 1.8% showed incomplete presentation. CALs were observed in 3.3% (4.0% of males, 2.3% of females; P = 0.080). The ORs of CALs among patients <11 months old (3.0, 95% CI 1.4–6.6) and those >48 months old (3.1, 95% CI 1.5–6.6) were significantly higher than values in 11- to 48-month-olds.ConclusionsThe effect of patient age on the development of CALs was found to be U-shaped, with the bottom at ages 11 to 48 months. This finding was based on a 13-year cohort of consecutive KD cases in a specific area with little selection bias and is consistent with previously reported results.

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Background: Epidemiological studies show a U-shaped tendency in Kawasaki disease (KD)-related coronary artery abnormalities (CAAs) across age categories. Since studies suggest seasonal variations in KD onset, this study aimed to clarify the epidemiologic features of CAAs, considering the seasons of KD-occurrence. Methods: We analyzed 2,106 (males = 1,215, females = 891) consecutive KD cases from October 1999 through September 2017 using our electronic database of annual surveys, targeting all hospitals with pediatric departments across Wakayama, Japan. The primary outcome was the presence=absence of CAAs measured by echocardiography 1 month after KD onset. Odds ratios (ORs) and 95% confidence intervals (CIs) of combined patient age and sex for CAAs were calculated using logistic regression models adjusted for four seasons. Results: The median age was 25 (range, 1-212) months. The proportion of males decreased with increasing age. The youngest age group (<6 months) showed an inverse summer=autumn to winter=spring ratio (>1.0) in KD-occurrence. CAAs were observed in 2.8% of cases (males = 3.4%, females = 2.1%), which significantly lessened in summer than in other seasons. Moreover, 50% (n = 4=8) of cases with giant aneurysms experienced KD in autumn. Adjusted ORs for CAAs among males aged ≥60 months (3.0; 95%, CI 1.2-7.5) and females aged <6 months (3.6; 95%, CI 1.1-11.8) were significantly higher than those among males aged 12-35 months. Conclusions: Cumulative 18-year data of consecutive KD cases from one area suggest the influence of interactions between patient age and sex on the development of KD-related CAAs. The season of KD-occurrence may reflect the diversity of agents.