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Introduction: Kawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (Fc γ Rs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA., Materials and Methods: We investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case-control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search., Results: FCGR2A- p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case-control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B- NA2 haplotype (OR = 2.15, 95% CI = 1.15-4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk., Discussion: FCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Uittenbogaard, Netea, Tanck, Geissler, Buda, Kowalczyk-Domagała, Okarska-Napierała, van Stijn, Tacke and US Kawasaki Disease Genetics Consortium, Burgner, Shimizu, Burns, Kuipers, Kuijpers and Nagelkerke.)

Kawasaki disease (KD) is an acute systemic vascular disease complicated by coronary artery injury. Although polymorphisms in prostaglandin-endoperoxide synthase 1 ( PTGS1 ) are being increasingly explored in cardiovascular diseases, little is known regarding the connection between PTGS1 polymorphisms and KD risk. We evaluated 834 KD patients and 1474 healthy controls to explore the relationship between PTGS1 polymorphisms (rs1330344 and rs5788) and KD risk. Our results showed that the rs1330344 CC genotype was significantly associated with KD risk and coronary artery injury in children with KD. In combined analysis, individuals with 1-2 unfavorable genotypes had an increased risk of KD, compared with those with no risk genotype. Stratified analysis indicated that the rs1330344 CC genotype is strongly associated with increased risk of KD in children aged ≤60 months and females. Moreover, carrying 1-2 of these SNP genotypes had a higher risk of KD than those who harbored none of them in children ≤60 months of age and females; the risk of coronary artery dilatations/small aneurysms and medium/giant aneurysms was also significantly increased in KD patients. In summary, the PTGS1 rs1330344 CC genotype is associated with increased susceptibility to KD, which may contribute to KD pathogenesis and serve as a genetic biomarker.

Objectives: Kawasaki disease (KD) is a commonly acquired pediatric systemic vasculitis disease resulting in coronary artery aneurysm (CAA). The relationship between the ITPKC polymorphism (rs7251246) and the severity and susceptibility to KD in the Han Chinese population in Southern China remains unclear., Methods: We enrolled 262 children as controls and 221 children with KD (46 [20.8%] with intravenous immunoglobulin resistance and 82 [37.1%] with CAA). The relationship between the ITPKC rs7251246 polymorphism, KD susceptibility, and CAA formation was investigated., Results: While the ITPKC rs7251246 T>C polymorphism was not significantly associated with KD susceptibility, it was significantly related to the CAA risk in children with KD [CC/CT vs. TT: adjusted odds ratio [OR] 2.089, 95% confidence interval [CI] 1.085-4.020]. Male children with the rs7251246 CT/TT genotype had a significantly lower risk of thrombosis [CT/TT vs. CC: adjusted OR 0.251, 95% CI 0.068-0.923]. Children with KD, especially those with CAA, had significantly downregulated ITPKC mRNA compared to healthy children. ITPKC mRNA levels were lower in children with CAA who developed thrombosis ( P =0.039). In children with KD, the CC genotype showed lower mRNA levels of ITPKC ( P =0.035)., Conclusion: The ITPKC rs7251246 T>C polymorphism may be a risk factor for CAA and thrombosis in children with KD in the Han Chinese population, likely due to differences in mature mRNA levels caused by interference of RNA splicing. Dual antiplatelet therapy for thrombosis is recommended for male children with the rs7251246 CC genotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Yuan, Pang and Su.)

Kawasaki disease (KD), a rare multisystem inflammatory condition that predominantly affects children under six years of age, is the leading cause of childhood-acquired heart disease in developed countries. The pathogenesis is unknown, but studies support that an infectious stimulus triggers an autoimmune reaction in a genetically susceptible child. Recent studies demonstrated an association with autoantibody response to Del-1 (also known as EDIL3) in children with KD. Del-1 is an extracellular matrix protein that is expressed both in macrophages and vascular endothelium. Del-1 has an anti-inflammatory role by preventing leucocyte migration to inflammatory sites. Del-1 has two expression variants and genetic variants of Del-1 have been associated with the risk of intracranial aneurysms. Due to the physiologic plausibility for a role during KD, we chose to assess if autoantibodies against DEL-1 are seen in a larger cohort of children with KD and to assess if responses correlated to aneurysm formation. Contrary to prior findings, in comparison to febrile controls, autoantibodies were not overall higher in children with KD. Elevation in Post-IVIG samples in comparison to pre-IVIG and convalescent samples supports the commonality of anti-Del-1 antibodies. Autoantibodies were notably lower in children with KD who had coronary Z score elevations in comparison to those who did not., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Background: Kawasaki disease (KD) is a kind of vasculitis predominantly afflicting children younger than five. Although intravenous immunoglobulin (IVIG) has been regarded as the first-line therapy, there are some children unresponsive to it, resulting in higher risk of coronary artery aneurysms (CAA), the most severe complication of KD. Pyroptosis is an inflammatory apoptosis, which resembles the traits of IVIG-resistance. Therefore, our research aims to find relationships between KD with IVIG-resistance and pyroptosis, and provide the underlying mechanisms of IVIG-resistance., Methods: The transcriptome data of three datasets were downloaded from Gene Expression Omnibus (GEO) database. CIBERSORTx and WGCNA were combined to identify the coexpression gene network correlated with the up-regulated immune cells in KD, using differentially expressed genes (DEGs) overlapped in GSE68004 and GSE73461. The key genes in hub module were intersected with pyroptosis-related genes (PRGs). Then KD patients were divided into subgroups according to the expression of remaining genes, along with the construction of risk score (RS) based on the least absolute shrinkage and selection operator (LASSO) regression analysis. Besides, we explored the clinical value of RS between IVIG-responsive and -resistant KD patients in GSE16797. In addition, the biological pathways between subgroups were evaluated using Gene Set Variation Analysis (GSVA)., Results: A total of 4246 DEGs and three immune cells, including Monocytes, M0 macrophage, and neutrophils, were analyzed with P < 0.05 between KD and healthy controls (HCs). The lightcyan module was the hub module based on WGCNA, and only NLRC4, CASP1, CASP4, GSDMD, IL1B and PYCARD in the hub module were overlapped with PRGs. Then KD patients in GSE68004 were stratified into two clusters on the basis of the expression levels of six genes. RS was built with five out of six genes (exclude PYCARD) according to the LASSO analysis, which could differentiate C1 from C2, IVIG-responsive from -resistant KD patients. Besides, the high-risk group (C1) tended to be with increased levels of inflammation, immune responses and infiltration of neutrophils according to the analysis of GSVA and CIBERSORTx., Conclusion: We built a pyroptosis-related RS to evaluate the degree of pyroptosis and infiltrating immune cells in subgroups of KD, and associated it with the responsiveness to IVIG, which might help us to further understand the pathological process during IVIG-nonresponse., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Accumulating evidence suggests that several microRNA (miRNA) polymorphisms are closely associated with disease susceptibility or progression, such as in Kawasaki disease (KD). Our previous studies revealed the association of miR-149 rs2292832 T>C and miR-196a2 rs11614913 C>T polymorphisms with KD susceptibility. The present study further focused on the relationship between three miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and the risk of coronary artery aneurysm (CAA) in southern Chinese KD patients., Methods: We evaluated 318 KD patients with CAAs and 784 patients without CAAs. TaqMan assays were used to estimate genotyping and analyze the relationship between miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and risk associations of CAA by odds ratios (ORs) and 95% confidence intervals (CIs)., Results: We found that the miR-149 rs2292832 TC/CC genotype increased the CAA risk (adjusted OR = 1.53, 95% CI = 1.15-2.03, p = 0.003 for TC, adjusted OR = 1.63, 95% CI = 1.08-2.47, p = 0.021 for CC), whereas the miR-499a rs3746444 AG genotype decreased the CAA risk in KD patients (adjusted OR = 0.33, 95% CI = 0.25-0.45 p ≤ 0.001). Moreover, patients carrying two or three of these single nucleotide polymorphism (SNP) genotypes (rs2292832 TC/CC and rs11614913 TT and rs3746444 AA) had a higher risk for CAA than those who harbored only zero or one of these SNP genotypes., Conclusions: Our results demonstrated that the miR-149 rs2292832 T>C polymorphism increased the risk of CAA in KD patients and that the miR-499a rs3746444 A>G polymorphism decreased the risk of CAA in KD patients. Further studies with larger sample sizes and different centers are needed to confirm the findings of the present study., (© 2021 The Authors. The Journal of Gene Medicine published by John Wiley & Sons Ltd.)

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13., (© 2021. The Author(s).)

Kawasaki disease, known as mucocutaneous lymph node syndrome, is a multi-system disease of unknown aetiology that occurs in young children under 5 years of age. The recurrence rate of Kawasaki disease is as rare as 1-3%. Especially in cases with coronary artery involvement, recurrent Kawasaki disease should be investigated in terms of underlying rheumatologic diseases such as periodic fever syndromes, microscopic polyangiitis, polyarteritis nodosa, and systemic-onset juvenile arthritis. In this study, we report homozygote mutations in mevalonate kinase and familial Mediterranean fever genes in a recurrent Kawasaki disease with coronary dilatation.

Background: Kawasaki disease (KD) is characterized as a self-limited systemic vasculitis. C1q/tumor necrosis factor-related protein-1 (CTRP1) had been associated with the occurrence of vasculitis in KD. Methylation at the promoter region of certain genes was reported to be involved in the development process of KD. This study aims to investigate the methylation levels of CTRP1 in KD, as well as, its potential to predict coronary artery aneurysms (CAAs)., Methods: 31 patients with KD and 14 healthy controls (HCs) were recruited into this study. The KD group was further divided into KD with CAA (KD-CAAs) group and KD without NCAAs (KD-NCAAs) group. Methylation levels of CpG sites were determined by MethylTarget sequencing, a method that uses multiple targeted CpG methylation analysis., Results: The methylation levels of CTRP1 promoter region in the KD group were lower than that in the HC group at all predicted CpG sites, especially at sites 34, 51, 69, 79, 176 and 206. Compared with KD-CAAs group, the methylation levels of almost every CpG sites of CTRP1 were increased in the KD-NCAAs group, with site 69 and 154 found to be strongly related to the occurrence of CAAs., Conclusions: The difference in methylation levels of CTRP1 promoter may be involved in the development process of KD, and may be a potential predictive marker for the occurrence of CAAs., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest and no authors' financial ties to products in the study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose of Review: Kawasaki disease is a childhood vasculitis of unknown origin, whose major complication is the development of coronary artery aneurysms (CAA). The purpose of this review is to provide an overview on the most recent evidence on the pathogenesis, diagnosis and treatment options of Kawasaki disease summarizing the most relevant studies published in the last year., Recent Findings: Several genetic polymorphisms leading to Kawasaki disease susceptibility have been identified, mostly related to immune system regulation; potential external triggers are being investigated by environmental epidemiology studies. A new diagnostic test based on trascriptomics has been tested with promising preliminary results. With regards to first-line treatments, the real effectiveness of high-dose aspirin remains a matter of debate. For refractory cases, the ones at the highest risk for developing CAA, promising results come from the use of biologic agents, especially TNF and IL-1 blockers., Summary: Recent literature has provided interesting insights on the various factors involved in the complex scenario behind the pathogenesis of Kawasaki disease, especially genetic ones. Novel diagnostic tests and new evidence on the use of biologic agents in Kawasaki disease are emerging, but further evidence is needed to permit early diagnosis and effective treatment of this condition.

Beckground: The current study aims to investigate whether miR-937 can be used as a diagnostic biomarker in peripheral blood mononuclear cells (PBMCs) for children with Kawasaki disease (KD) with or without coronary artery dilation (CAD)., Methods: Gene chip technology was used to screen miRNAs differentially expressed between KD children and normal healthy children. Furthermore, real time PCR was carried out to validate the expression of miR-937 in 50 children with KD (25 cases with and 25 cases without CAD) and 25 healthy children. Meanwhile, target genes of miR-937 were analyzed using TargetScan and dual luciferase reporter assay., Results: First, 20 miRs with significantly differentially expressed mononuclear cell (PBMCs) in peripheral blood between children with KD and normal healthy children were identified by gene chip technology. Real time PCR analysis validated that the expression of miR-937 decreased most significantly among all differentially expressed miRNAs. Secondly, miR-937 was down-regulated significantly before treatment with gamma globulin (IVIG), while its expression was significantly up-regulated after IVIG treatment. In addition, the expression of miR-937 in KD children with CAD was significantly lower than that of KD children without CAD. Person's correlation assay showed that miR-937 negatively correlated with CAD. Dual luciferase reporter assay indicated that IL-1β was a target gene of miR-937., Conclusions: In summary, miR-937 in PBMCs was involved in the occurrence and development of KD, which provides new ideas for the prevention and treatment of KD coronary artery dilation.

Kawasaki disease (KD) is a self-limiting systemic vasculitis of unknown etiology. KD is often complicated by coronary artery aneurysms (CAAs), which develop in about 20-25% of untreated children and 3-5% of children treated with intravenous immunoglobulin therapy. To identify the risk loci for CAA susceptibility in patients with KD, we performed a genome-wide association study (GWAS) using our previous Illumina HumanOmni1-Quad BeadChip data (296 KD patients) and a new replication study in an independent sample set (713 KD patients) by grouping KD patients without CAA (control) versus KD patients with extremely large aneurysms (diameter ≥ 5 mm) (case). Among 44 candidate single -nucleotide polymorphisms (SNPs) selected from the initial GWAS data (33 cases vs. 215 controls), a SNP (rs899162) located 7 kb upstream of the TIFAB gene on chromosome five was replicated in an independent sample (12 cases vs. 532 controls). In the combined analysis (45 cases vs. 747 controls), the SNP (rs899162) showed a highly significant association with CAA formation (diameter ≥ 5 mm) in patients with KD (odds ratio = 3.20, 95% confidence interval = 2.02-5.05, P combined  = 1.95 × 10 -7 ). These results indicate that the TIFAB gene may act as a CAA susceptibility locus in patients with KD.

Background: Activated-platelet increases the risk of thrombosis in Kawasaki disease (KD) patients with a coronary artery aneurysm (CAA). The ADP pathway is one of the platelet activation and aggregation pathways. The P2RY12 gene encodes the ADP receptor that is highly concentrated on platelets. However, few studies have reported on P2RY12 in relation to KD susceptibility with or without CAA., Methods: We recruited 1335 healthy controls and 776 KD patients, including 103 with CAA, and selected five P2RY12 polymorphisms: rs9859538, rs1491974, rs7637803, rs6809699 and rs2046934. The present study focused on the relationship between the P2RY12 polymorphisms and KD with or without CAA., Results: Among all of the selected polymorphisms, single-locus analysis showed no significant association between the P2RY12 polymorphism and KD susceptibility. However, we found a significant relationship between rs7637803 and CAA risk in KD patients [CT versus CC: odds ratio (OR) = 0.41, 95% confidence interval (CI) = 0.22-0.75; p = 0.0041; TT versus CC: OR = 2.90, 95% CI = 1.12-7.46; p = 0.0276]. Stratification analysis by age in KD patients indicated that the rs7637803 TT genotype increased CAA formation risk among children aged (OR = 3.90, 95% CI = 1.42-10.69; p = 0.0081) and increased the onset risk of CAA in males (OR = 6.28, 95% CI = 2.01-19.65; p = 0.0016). The combined effect of the five selected P2RY12 risk genotypes with the KD patients compared to non-mutated P2RY12 genotypes (score: 0) showed that patients with P2RY12 genotype polymorphisms (score: 1-5) had a significantly increased CAA risk (p = 0.0086). Stratification analysis for the severity of CAA found that the rs7637803 TT genotype reduced giant CAA (GCAA) risk (OR = 4.60, 95% CI = 1.70-12.41; p = 0.0026)., Conclusions: The results of the present study indicate that the P2RY12 rs7637803 genotype might be used as a biomarker to predict the occurrence of GCAA., (© 2018 John Wiley & Sons, Ltd.)

Background: Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility., Methods and Results: To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways (P<5×10 - 4 ). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport (P=1.05×10 - 4 ). Three single nucleotide polymorphisms in solute carrier family 8, member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis P=0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (P=0.029). NCX1, the protein encoded by SLC8A1, was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele., Conclusions: Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD., (© 2016 American Heart Association, Inc.)

Kawasaki disease (KD) or Kawasaki syndrome is known as a vasculitis of small to medium-sized vessels, and coronary arteries are predominantly involved in childhood. Generally, 20-25% of untreated with IVIG and 3-5% of treated KD patients have been developed coronary artery lesions (CALs), such as dilatation and aneurysm. Understanding how coronary artery aneurysms (CAAs) are established and maintained in KD patients is therefore of great importance. Upon our previous genotyping data of 157 valid KD subjects, a genome-wide association study (GWAS) has been conducted among 11 (7%) CAA-developed KD patients to reveal five significant genetic variants passed pre-defined thresholds and resulted in two novel susceptibility protein-coding genes, which are NEBL (rs16921209 (P = 7.44 × 10(-9); OR = 32.22) and rs7922552 (P = 8.43 × 10(-9); OR = 32.0)) and TUBA3C (rs17076896 (P = 8.04 × 10(-9); OR = 21.03)). Their known functions have been reported to associate with cardiac muscle and tubulin, respectively. As a result, this might imply their putative roles of establishing CAAs during KD progression. Additionally, various model analyses have been utilized to determine dominant and recessive inheritance patterns of identified susceptibility mutations. Finally, all susceptibility genes hit by significant genetic variants were further investigated and the top three representative gene-ontology (GO) clusters were regulation of cell projection organization, neuron recognition, and peptidyl-threonine phosphorylation. Our results help to depict the potential routes of the pathogenesis of CAAs in KD patients and will facilitate researchers to improve the diagnosis and prognosis of KD in personalized medicine.

Kawasaki disease (KD) is an acute, inflammatory, and self-limited vasculitis affecting infants and young children. Coronary artery aneurysm (CAA) formation is the major complication of KD and the leading cause of acquired cardiovascular disease among children. To identify susceptible loci that might predispose patients with KD to CAA formation, a genome-wide association screen was performed in a Taiwanese KD cohort. Patients with both KD and CAA had longer fever duration and delayed intravenous immunoglobulin treatment time. After adjusting for these factors, 100 susceptibility loci were identified. Four genes were identified from a single cluster of 35 using the Ingenuity Pathway Analysis (IPA) Knowledge Base. Silencing KCNQ5, PLCB1, PLCB4, and PLCL1 inhibited the effect of lipopolysaccharide-induced endothelial cell inflammation with varying degrees of proinflammatory cytokine expression. PLCB1 showed the most significant inhibition. Endothelial cell inflammation was also inhibited by using a phospholipase C (PLC) inhibitor. The single nucleotide polymorphism rs6140791 was identified between PLCB4 and PLCB1. Plasma PLC levels were higher in patients with KD and CC+CG rs6140791genotypes, and these genotypes were more prevalent in patients with KD who also had CAA. Our results suggest that polymorphism of the PLCB4/B1 genes might be involved in the CAA pathogenesis of KD.

Background: Kawasaki disease (KD) is an acute, self-limited vasculitis in infants and young children. Interleukin-10 (IL-10) is a potent cytokine that exerts pleiotropic effects on immunoregulation and inflammation. Elevated IL-10 serum levels have been reported in the KD patients., Methods: In this study, we investigated whether IL-10 genetic polymorphisms contribute to coronary artery aneurysm (CAA) development among KD patients in Taiwan. A total of 58 KD patients with CAA and 277 unrelated healthy children matched for sex and age were enrolled for this study., Results: Higher G allele frequencies of IL-10 at -1082 position were observed in KD patients with CAA compared to the controls (P = 0.016, OR: 2.86, 95% CI, 1.17-6.98). In addition, higher IL-10 GCC haplotype frequencies were also observed in KD patients with CAA (P = 0.016, OR: 2.85, 95% CI, 1.17-6.98)., Conclusion: Our data support the possibility that IL-10 gene polymorphisms may be related with CAA development of KD in Taiwanese population., (© 2014 Wiley Periodicals, Inc.)

Background: Kawasaki disease (KD) patients who experience a cardiovascular complication known as a coronary artery aneurysm (CAA) are at high risk of developing ischemic heart disease, which may lead to sudden death. The etiology of CAA in KD patients is unclear, and this study aims to clarify the relationship between steroid receptor coactivator-1 (SRC-1) gene polymorphisms and CAA pathogenesis., Methods: We investigated four SRC-1 gene polymorphisms (rs11894248, rs17791703, rs7572475, and rs9309308) and their correlation with KD with CAA susceptibility in 327 Taiwanese people (279 KD patients without CAA and 48 KD patients with CAA)., Results: The results indicated a statistically significant difference in genotype and allele frequency distributions at the SRC-1 four single nucleotide polymorphisms (SNPs) between KD patients with and without CAA (P < 0.01). Additionally, Smad3 gene polymorphism (rs12901071) is well known to be associated with KD patients. In our results, Smad3 SNP did not provide a statistically significant difference between KD patients with and without CAA., Conclusion: Our data show that SRC-1 polymorphisms may be the underlying cause of CAA; therefore, the polymorphisms examined in this study warrant further investigation., (© 2014 Wiley Periodicals, Inc.)

Kawasaki disease (KD) is pediatric systemic vasculitis with the classic complication of coronary artery aneurysm (CAA). It is the leading cause of acquired cardiovascular diseases in children. Some severe cases present with multi-organ involvement or neurological dysfunction. To identify the role of the glutamate receptor, ionotropic, N-methyl-d-aspartate 3A (GRIN3A) in KD, we investigated genetic variations in GRIN3A in a Taiwanese cohort of 262 KD patients (76 with and 186 without CAA complications). We used univariate and multivariate regression analyses to identify the associations between clinical characteristics and GRIN3A genetic variations in KD. According to univariate regression analysis, CAA formation in KD was significantly associated with fever duration (p < 0.0001), first Intravenous immunoglobulin (IVIG) used (days after day one of fever) (p < 0.0001), and the GRIN3A (rs7849782) genetic variant (p < 0.001). KD patients with GG+GC genotype showed a lower rate of developing CAA (GG+GC genotype: odds ratio = 0.26; 95% CI = 0.14-0.46). Significant associations were identified between KD with CAA complication and the GRIN3A (rs7849782) genetic variant by using multivariate regression analysis. Specifically, significant correlations were observed between KD with CAA complications and the presence of GG+GC genotypes for the GRIN3A rs7849782 single-nucleotide polymorphism (full model: odds ratio = 0.25; 95% CI = 0.14-0.46). Our results suggest that a polymorphism of the GRIN3A gene may play a role in KD pathogenesis.

Kawasaki disease (KD) is often complicated by coronary artery lesions (CALs), including aneurysms. Because of the complications associated with KD, this disorder is the leading cause of acquired heart disease in children from developed countries. To identify genetic loci that confer a higher risk of developing CALs, we performed a case-control association study using previous genome-wide association study data for samples from KD cases only (n=186) by grouping KD patients without CALs (control: n=123) vs KD patients with extremely large aneurysms (diameter>5 mm) (case: n=17). Twelve loci with one or more sequence variants were found to be significantly associated with CALs (P<1 × 10(-5)). Of these, an SNP (rs17136627) in the potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2 (KCNN2) at 5q22.3 was validated in 32 KD patients with large aneurysms (diameter>5 mm) and 191 KD patients without CALs (odds ratio (OR)=12.6, P(combined)=1.96 × 10(-8)). This result indicates that the KCNN2 gene can have an important role in the development of coronary artery aneurysms in KD.

Background: Kawasaki disease (KD) involves a complex interaction of immunoinflammatory process, cytokine activation, and genetic factors. We aimed to investigate whether genetic variations in a major histocompatibility complex (MHC) class could be used as markers of susceptibility in KD and coronary artery aneurysm lesions (CALs)., Methods: Individuals were divided into following groups: (1) normal controls; (2) KD with CAL; (3) KD without CAL. Polymorphisms for MHC class I chain-related genes A (MICA) (rs2301747, rs2256184, rs2848716), MICB (rs2855804, rs3132464, rs2516400), BAT3 (rs750332), MSH5 (rs1150793), and chromosome 6 open reading frame 27 (C6orf27, rs707928) were genotyped with polymerase chain reaction and the TaqMan(®) allelic discrimination assay. Genotypes, alleles, and haplotype in each group were compared., Results: Genotype and allele frequency of MICB*rs2516400 polymorphisms in each group were significantly different. MICB (rs2516400)*C-related genotypes/alleles are correlated with development of KD and CAL. Proportions of rs2516400*TT/TC/CC were (1) 1/39/60%, (2) 0/0/100%, and (3) 0/0/100%. Other single-nucleotide polymorphisms were not associated with KD susceptibilities. Haplotypes (rs2301747-rs2256184-rs2848716-rs2855804-rs3132464-rs2516400-rs750332-rs1150793-rs707928) G-G-G-C-T-C-T-A-A, C-A-G-T-T-C-T-A-A, and G-G-G-C-C-C-T-A-A were associated with higher susceptibilities for KD. The G-G-G-T-T-T-T-G-G and C-G-G-T-T-T-T-A-A haplotypes were associated with lower susceptibilities., Conclusion: MICB*rs2516400 polymorphisms and some MHC class I-related haplotypes are associated with KD susceptibility. MICB and MHC class I genetic variations might contribute to the pathogenesis of KD and CAL.

Background and Aims: The Mexican population has a distinct capacity for the expression of tumor necrosis factor (TNF), a cytokine that plays a cardinal role in Kawasaki disease (KD), particularly in those who develop coronary aneurysms. It is important to identify, in Mexican pediatric patients, the association of the frequency of TNF. This study determined the association of TNF -308 and lymphotoxin-alpha (LTA) +252 polymorphisms in Mexican pediatric patients with KD and coronary aneurysms (CA)., Methods: We conducted a cross-sectional, analytical study in 48 children with KD, 22 with CA. Control samples were obtained from 61 aged-matched children. We took a peripheral blood sample and extracted genomic DNA from all children participating in the study. Using restriction factor length polymorphism-polymerase chain reaction (RFLP-PCR), we performed determination of TNF -308 and LTA +252., Results: There was no difference in frequency between the study groups for genotype LTA +252 (OR 0.37, 95% CI, 0.06-2, p = 0.44) or between groups for KD with or without coronary aneurysms for both polymorphisms. In subjects with KD, we did not observe the heterozygous genotype of TNF -308, the difference being significant (OR 12, 95% CI, 4.8-30.4, p = 0.0001) using the χ(2) test with the continuity correction on comparison with the control group., Conclusions: Comparative analysis by group did not show a significant difference in the frequency of the alleles and genotypes between KD with CA vs. KD without CA vs. controls, for both TNF -308 and LTA +252., (Copyright © 2011 IMSS. Published by Elsevier Inc. All rights reserved.)

Kawasaki disease (KD) is the most common form of pediatric vasculitis. Though its etiology is unknown, researchers have suggested that it is related to genetics. The inositol 1,4,5-triphosphate receptor type 3 (ITPR3) gene has a strong association with the development of type 1 diabetes and, plays a critical role in the development of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Graves' disease. The aim of study is to examine the association of ITPR3 polymorphisms with KD risk in Taiwanese children. This study evaluates the single nucleotide polymorphisms (SNP) rs2229634 in the ITPR3 gene with KD in a case-control study involving 93 KD patients and 680 healthy, gender- and age-matched controls. The frequency of the rs2229634 T/T genotype was significantly higher in KD patients with coronary artery aneurysm (CAA) than in patients without CAA [odds ratio (OR) = 2.56, 95% confidence interval (95% CI) = 1.35-4.88, P = 0.004]. In addition, KD patients with the T/T genotype elevated mean serum levels of C-reactive protein compared with patients with the C/C or C/T genotype (12.2 mg dL(-1) vs. 8.5 mg dL(-1) , P = 0.036). In conclusion, the results of this study suggest that the rs2229634 SNP in the ITPR3 gene is associated with the risk of CAA formation in Taiwanese KD patients., (© 2010 Blackwell Publishing Ltd.)

Capsule: HLA-B associated transcript (BAT) 2, 3, and 5 polymorphisms and haplotypes are associated with Kawasaki disease (KD) and coronary artery aneurysm (CAA) formations., Objective: KD, an acute vasculitis with unknown etiology, involves a complex interaction of immuno-inflammatory process, cytokines activation, and genetic factors. We aimed to investigate if genetic variants of human lymphocyte antigen (HLA)-BAT2, 3, and 5 (BAT2, 3, and 5) could be used as markers of susceptibility in KD and CAA., Methods: Individuals were divided into three groups: (1) normal controls; (2) KD with CAA; and (3) KD without CAA. Polymorphisms for BAT2 (-8671, 16483), BAT3 (8854, 2-24), and BAT5 (22655, 9569) were genotyped by PCR system with TaqMan allelic discrimination assay. Genotype/allelic frequencies and haplotypes (BAT2(-8671)-BAT2(16483)-BAT3(8854)-BAT3(2-24)-BAT5(22655)-BAT5(9569)) in each group were compared., Results: Genotype distribution and allele frequency of BAT2 -8671, BAT3 8854, and BAT5 22655, 9569 polymorphisms in each group were significantly different. BAT2 -8671*G, BAT3 8854*C, BAT5 22655*C, and 9569*A-related genotypes and alleles are correlated with the developments of KD and CAA. BAT haplotypes of ATTGTG and ATCATG are associated with higher susceptibilities of KD with CAA susceptibility., Conclusion: BAT2 -8671, BAT3 8854, and BAT5 22655, 9569 polymorphisms as well as BAT haplotypes (ATTGTG and ATCATG) might be associated with higher KD susceptibility and CAA formation. HLA-B region polymorphisms might contribute to the pathogenesis of KD and CAA.

Objective: Kawasaki disease (KD) is a pediatric systemic vasculitis of unknown cause for which a genetic influence is supposed. The purpose of this study was to identify possible genetic variants in the major histocompatibility complex (MHC) region that are associated with KD and the development of coronary artery aneurysms (CAAs) in a Taiwanese population., Methods: The 168 genetic variants covering the MHC locus were analyzed in an association study of a Taiwanese cohort of 93 KD patients and 680 unrelated healthy children matched for sex and age with the study patients., Results: Eleven single-nucleotide polymorphisms (SNPs) were associated with the occurrence of KD. The SNP located at the 3'-untranslated region of HLA-E (rs2844724) was highly associated (P < 1 x 10(-7)). In addition, the frequency of the C allele was higher in KD patients without CAAs than in controls (P < 0.001) due to a significantly increased frequency of the CC and CT genotypes. Plasma levels of soluble HLA-E were significantly higher in KD patients than in controls regardless of the presence of CAAs. Furthermore, there was a trend toward higher plasma levels of soluble HLA-E in KD patients with the CT and TT genotypes of the HLA-E gene polymorphism., Conclusion: Our results suggest that the HLA-E gene polymorphism may play a role in the pathogenesis of KD.

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc&#95;3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc&#95;3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.

Background: Kawasaki disease (KD) causes coronary artery disease (CAD) in children. In addition, a history of KD is suspected to be a risk factor for the development of atherosclerotic heart disease in the future. Histological senescence changes are a common denominator in atherosclerotic lesions in adults, so the present study investigated whether histological senescence changes had already occurred in KD aneurysm., Methods and Results: KD coronary aneurysms and internal mammary arteries retrieved from 5 children with KD (3, 4, 5, 6, and 11 years old, respectively) who underwent coronary artery bypass grafting, as well as giant coronary aneurysm size-reducing operations, were analyzed. Senescence-associated strong beta-galactosidase activity was observed in KD aneurysms, but not in the internal mammary arteries. An immunohistochemical analysis of the KD aneurysm using anti-CD31, anti-endothelial nitric oxide synthetase (eNOS), anti-vascular adhesion molecule-1 (VCAM-1), and anti-monocyte chemoattractant protein-1 (MCP-1) showed vascular endothelium CD31 staining, decreased staining of eNOS and strong staining of MCP-1 and VCAM-1. cDNA microarray gene expression profiling revealed increased MCP-1 expression in the KD aneurysm, a finding confirmed by quantitative polymerase chain reaction., Conclusions: Histological features of senescence and active remodeling gene expression show that the KD aneurysm is not a silent vasculitis terminal. The future fate of KD aneurysms, including atherosclerosis, should be monitored carefully.

Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects the coronary artery. Interleukin-10 (IL-10) is a key proinflammatory cytokine, and a polymorphism near the major transcriptional start site of the IL-10 gene was shown to influence IL-10 production in vitro. This study investigated the association of the IL-10 promoter polymorphism with KD and its clinical parameters in Korean children. A total of 194 children with congenital heart disease (CHD) and 95 children with KD were included in this study. IL-10 (-627 A/C) polymorphism genotypes were determined using the single-base extension method. There was no difference in the allele frequencies of IL-10 (-627 A/C) polymorphism between CHD children and KD children. KD children with one or two copies of the IL-10 (-627C) allele showed significantly lower albumin levels (p = 0.020) and higher frequencies of early coronary artery aneurysm [62.22% versus 37.78%, adjusted odds ratio (aOR) = 3.50, 95% confidence interval (CI): 1.50-8.16] compared with KD children with the common IL-10 (-627A) allele. These findings suggest that the IL-10 (-627 A/C) promoter polymorphism might be a genetic marker for the risk of early coronary artery complication in KD.

The etiology and pathogenesis of Kawasaki disease (KD) is largely unknown. Certain demographic factors and laboratory findings are predictive of the development of coronary artery (CA) aneurysms. The objectives of this study were to determine the epidemiology of KD patients in an urban hospital and determine risk factors associated with their development of CA abnormalities. A longitudinal case series of KD patients admitted to Children's National Medical Center from 1990 to 2002 was examined. Age, sex, ethnic background, duration of fever prior to diagnosis, address, month diagnosed, and CA abnormalities (ectasia or aneurysms) on echocardiography were recorded. Median household income was obtained from the U.S. Census Bureau Web site. The Student t-test, logistic regression analyses, and the Kruskal-Wallis test were used, with significance assumed at p < 0.05. A total of 302 patients were evaluated. CA abnormalties were found in 27 patients (9%), with aneurysms identified in 13 patients (4%). Age was 2.9 +/- 2.4 years (range, 2 months to 14 years). A total of 51 patients (16%) were < or =1 year and 35 patients (12%) were > or =5 years. Ethnic distribution was 54% (164) African American, 24% (72) Caucasian, 9% (29) Asian/Pacific Islander, 8% (23) Hispanic, and 5% (14) Middle Eastern. Only 2/164 (1.2%) African Americans developed CA aneurysms. Neighborhood median income of the cohort was $45,400 +/- $21,200 ($52,200 +/-$25,800 for patients with aneurysms). A total of 28% of cases clustered between December and January. Cases doubled annually in 1999-2001 compared to 1990-1998 (39 vs 19). Multivariate logistic regression found age between 1 and 5 years [p = 0.045; odds ratio, 0.31; 95% confidence interval (CI), 0.10-0.97] and African American race (p = 0.014; odds ratio, 0.15; 95% CI, 0.03-0.68) to be independently protective against CA aneurysms. Duration of fever prior to diagnosis, considered in 210 patients, was different between patients with and without aneurysms (11 +/- 5.3 vs 6.5 +/- 3.8 days, respectively, p = 0.0007). Multivariate logistic regression found fever longer than 5 days to be the only predictive factor associated with the development of aneurysms and any abnormality. African Americans had a shorter duration of fever than the rest of the cohort (6.03 vs 7.31 days), (p = 0.0087). The epidemiology of KD at our hospital is similar to that at other centers except for the predominance of African Americans with a shorter duration of fever prior to diagnosis and a decreased incidence of CA aneurysms compared to other ethnicities. The protective nature of African American ethnicity against the development of CA aneurysms raises speculation about the role of genetics and its interaction with immunity in the pathogenesis of KD.

Unlabelled: A 287 base pair insertion/deletion polymorphism in intron 16 of the angiotensin I converting enzyme (ACE) gene was examined by polymerase chain reaction in 36 Kawasaki disease patients (16 without coronary aneurysm, 20 with coronary aneurysm). A polymorphism in the ACE gene was characterized by three genotypes: two D alleles (genotype DD), two I alleles (genotype II), and heterozygous allele (genotype DI). Genotype II was found in 65% of the patients with aneurysm and 12.5% of those without aneurysm (P < 0.01, odds ratio 13.0, 95% confidence intervals)., Conclusion: Patients with Kawasaki disease and coronary aneurysm more often than expected had the genotype II suggesting that reactions induced by the type of ACE polymorphism predispose to coronary aneurysm formation.