We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.

Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

Background-Increased microvascular permeability is an initial step of Kawasaki disease (KD). We reported that vascular endothelial growth factor (VEGF) might play a role in the vascular leakage of KD. In fatal KD, plasma leakage was extensively documented at VEGF-positive microvessels. Increases in vascular leakage cause hypoalbuminemia and noncardiogenic edema. However, the prognostic impact of vascular leakage in KD remains unclear. Methods and Results-We compared 76 patients who became afebrile within 5 days after starting intravenous gamma globulin (IVGG) (2 g/kg over 5 days) (IVGG-responsive) with 27 patients who did not respond (IVGG-resistant). Baseline levels of serum VEGF and albumin were similar between the groups. After IVGG, VEGF levels increased (PϽ0.0001) and albumin levels decreased (PϽ0.00001) in both groups. However, the IVGG-resistant group had higher VEGF levels (Pϭ0.029) and severe hypoalbuminemia (PϽ0.00001) compared with the IVGG-responsive group. Coronary aneurysms were documented in 12 patients from the IVGG-resistant group but not in the IVGG-responsive group. Then IVGG-resistant patients were divided into 2 subgroups according to the presence (nϭ12) or absence (nϭ15) of coronary aneurysms. There was no difference between subgroups in age, sex, laboratory data including albumin, and retreated doses of IVGG. However, body weight gain after IVGG was documented in patients who subsequently developed coronary aneurysms (Pϭ0.003) but not in those who did not (Pϭ0.967). Conclusions-These

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

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.

Summary: Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder presenting with an elfin-like face, supravalvular aortic stenosis, a specific cognitivebehavioral profile, and infantile hypercalcemia. We encountered two WBS patients presenting with infantile spasms, which is extremely rare in WBS. Array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) analyses revealed atypical 5.7-Mb and 4.1-Mb deletions at 7q11.23 in the two patients, including the WBS critical region and expanding into the proximal side and the telomeric side, respectively. On the proximal side, AUTS2 and CALN1 may contribute to the phenotype. On the telomeric side, there are two candidate genes HIP1 and YWHAG. Because detailed information of them was unavailable, we investigated their functions using gene knockdowns of zebrafish. When zebrafish ywhag1 was knocked down, reduced brain size and increased diameter of the heart tube were observed, indicating that the infantile spasms and cardiomegaly seen in the patient with the telomeric deletion may be derived from haploinsufficiency of YWHAG. genesis 48:233-243, 2010. V V C 2010 Wiley-Liss, Inc.

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Objectives: Central blood pressure (CBP) can now be reliably measured noninvasively with a number of devices in adult; however, noninvasive assessment of CBP has not been validated in children and adolescents. The purpose of this study was to clarify the accuracy of noninvasive oscillometric CBP measurements in children and adolescents. Methods: This study included 60 patients with an average age of 7.9 ± 4.4 years (range 1–18 years) who underwent a cardiac catheterization. We compared CBP, estimated with a noninvasive oscillometric method using a Mobil-O-Graph, with simultaneous invasive recordings using a catheter in children and adolescents. Results: Comparison of the SBP values measured by the two methods, showing a linear correlation (r = 0.85; P < 0.0001) with the mean difference aortic SBP minus estimated central SBP of 2.0 ± 5.6 mmHg (95% limits of agreement = −9.0–13.1). In DBP values, there was a correlation (r = 0.72; P < 0.0001) with the mean difference aortic DBP minus estimated central DBP of −0.1 ± 6.4 mmHg (95% limits of agreement = −12.6–12.4). Sex and cardiac function did not affect central SBP estimation; however, the correlation between aortic and estimated central SBP in adolescents was better than that in children (r = 0.93, P < 0.0001 vs. r = 0.77, P < 0.0001), though the difference was not statistically significant (P = 0.483). Conclusion: Estimated CBP using Mobil-O-Graph in children and adolescents shows a certain degree of accuracy, which will be helpful in future for evaluating CBP in children and adolescents.