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Background Damage to the coronary arteries during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myointimal proliferation, and endothelial cell (EC) dysfunction. To understand the response of ECs to KD treatment, we studied the genome-wide transcriptional changes in cultured ECs incubated with KD sera before and after treatment with or without atorvastatin. Methods and Results RNA sequencing of human umbilical vein ECs incubated with pooled sera from patients with acute KD before or after treatment with intravenous immunoglobulin and infliximab revealed differentially expressed genes in interleukin-1, tumor necrosis factor-α, and inflammatory cell recruitment pathways. Subacute sera pooled from patients treated with intravenous immunoglobulin, infliximab, and atorvastatin uniquely induced expression of NOS3 , Kruppel like factor ( KLF2 , and KLF4 (promotes EC homeostasis and angiogenesis) and ZFP36 ring finger protein (ZFP36) and suppressor of cytokine signaling 3 (SOCS3) (suppresses inflammation), and suppressed expression of TGFB2 and DKK1 (induces endothelial-mesenchymal transition) and sphingosine kinase 1 (SPHK1) and C-X-C motif chemokine ligand 8 (CXCL8) (induces inflammation). Conclusions These results suggest that atorvastatin treatment of patients with acute KD may improve EC health, reduce mediators of inflammation produced by ECs, and block KD-induced myofibroblast proliferation.

Kawasaki disease (KD) is an acute systemic vasculitis that is most seriously complicated by coronary artery aneurysm (CAA). The polymorphisms of platelet endothelial aggregation receptor 1 (PEAR1), notably rs12041331 and rs12566888, were found to be closely related to cardiac disease. However, little is known regarding the connection between PEAR1 and KD. In this study, we genotyped PEAR1 rs12566888 and rs12041331 in 637 healthy infants and 694 KD patients (74 with CAA). Subsequently, odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the strength of their relationships. No significant differences in the frequency of rs12566888 or rs12041331 in PEAR1 were observed between KD and healthy controls. However, regardless of the statistical combination of rs12566888 genotype, the rs12041331 recessive inheritance model was associated with an increased risk of CAA after Bonferroni correction (for rs12041331, AA vs. GG/GA: adjusted OR = 2.37, 95% CI = 1.41-4.01, P = 0.009; combination of two recessive genotypes vs. combination of 0-1 recessive genotypes: adjusted OR = 2.39, 95% CI = 1.42-4.04, P = 0.009). This study suggests for the first time that PEAR1 polymorphisms did not indicate susceptibility for KD occurrence but the rs12041331 polymorphism was associated with increased risk of CAA formation in KD, and the functions of the gene warrant further research., (© 2018 John Wiley & Sons Ltd/University College London.)

Kawasaki disease is a multisystemic vasculitis that can result in coronary artery lesions. It predominantly affects young children and is characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and non-suppurative lymphadenopathy. Coronary artery involvement is the most important complication of Kawasaki disease and may cause significant coronary stenosis resulting in ischemic heart disease. The introduction of intravenous immunoglobulin decreases the incidence of coronary artery lesions to less than 5%. The etiopathogenesis of this disease remains unclear. Several lines of evidence suggest that an interplay between a microbial infection and a genetic predisposition could take place in the development of the disease. In this review, we summarize the state of the art of pathogenetic mechanisms of Kawasaki disease underscoring the relevance of haematological features as a novel field of investigation., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Kawasaki disease (KD) is now the most common cause of acquired cardiac disease in children due to permanent coronary artery damage with unknown etiology. The study sought to determine the role of blood microRNA miR-223 in KD and KD-induced injuries in vascular endothelial cells (ECs) as well as the mechanisms involved., Methods and Results: MicroRNA profiles in serum from patients with KD and from healthy controls were assessed by microarray analysis. We noted that multiple serum microRNAs were aberrantly expressed in KD, among them miR-223, which was the most upregulated abundant serum microRNA. We found that bone marrow-derived blood cells (leukocytes and platelets) were able to secrete miR-223 into serum. Vascular ECs had no endogenous miR-223; however, the blood cell-secreted serum miR-223 could enter into the vascular ECs in the vascular walls. The exogenous miR-223 had strong biological effects on EC functions via its target genes such as IGF1R. Interestingly, KD-induced EC injuries were related to increased miR-223 because they were inhibited by miR-223 knockdown. Finally, these observations were verified using miR-223 knockout mice and the chimeric mice generated by transplantation of bone marrow from miR-223 knockout mice into wild-type mice., Conclusions: In KD patients, the levels of blood cell-derived miR-223 in ECs are significantly increased. The increased miR-223 in ECs could work as a novel endocrine genetic signal and participate in vascular injury of KD. MiR-223 may provide a novel mechanism and a new therapeutic target for vascular complication of KD., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Kawasaki disease is a vasculitis most commonly afflicting children <5 years of age. Many autoimmune diseases are associated with up-regulation of T helper (Th) 17 cells, and down-regulation Treg cells. Few studies have examined the Th17/Treg expression in Kawasaki disease., Methods: Blood samples were obtained from 186 children with Kawasaki disease at 24 h before IVIG therapy, followed by 3 days and 21 days after IVIG therapy. Thirty children with an acute febrile infectious disease and 30 healthy children were obtained as control. Plasma levels of Th17- and Treg-related cytokines including IL-6, IL-17A, IL-10, TGF-β, and mRNA expression levels of RORγt and Foxp3 were tested., Results: Patients with Kawasaki disease had higher levels of plasma IL-17A (25.35 ± 3.21 vs 7.78 ± 1.78 pg/ml, P < 0.001) and IL-6 (152.29 ± 21.94 vs 38.63 ± 12.40 pg/ml, P < 0.001) when compared to the febrile control group. IVIG resulted in a reduction in IL-6 and IL-17A at both 3 and 21 days after IVIG therapy. FoxP3 levels increased significantly 3 days after IVIG therapy (2.28 ± 0.34 vs 0.88 ± 0.14, P < 0.001). IVIG resistance was associated with higher levels of IL-10 and IL-17A., Conclusion: Kawasaki disease was associated with higher IL-17A and IL-6, a cytokine profile similar to other autoimmune diseases. IVIG therapy resulted in increased expression of Treg-related FoxP3. IVIG resistance was associated with higher levels of IL-10 and IL-17A. Our findings provide further evidence that Kawasaki disease is an autoimmune-like disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: In Kawasaki disease (KD), a pediatric vasculitis of medium-sized arteries, the coronary arteries are most commonly affected. Angiopoietins and vascular endothelial growth factor (VEGF) play an important role in maintaining vascular homeostasis. Recently, we identified ANGPT1 and VEGFA as susceptibility loci for KD. This study was undertaken to fine-map these associations and to gain further insight into their role in this vasculitis of unknown etiology to further the search for improved diagnostic and therapeutic options., Methods: A total of 292 single-nucleotide polymorphisms (SNPs) located in VEGF and ANGPT and their receptors were genotyped in 574 families, including 462 trios. For replication, 123 cases and 171 controls were genotyped., Results: A significant association with KD susceptibility was observed with 5 SNPs in the ANGPT1 gene (most significantly associated SNP +265037 C>T; Pcombined=2.3×10(-7) ) and 2 SNPs in VEGFA (most significantly associated SNP rs3025039; Pcombined=2.5×10(-4) ). Both ANGPT1 +265037 C>T and VEGFA rs3025039 are located in 3' regulatory regions at putative transcription factor binding sites. We observed significantly down-regulated transcript levels of angiopoietin 1 (Ang-1) in patients with acute KD compared to patients with convalescent KD. In patients with acute KD, high serum protein levels of VEGF and Ang-2 were observed compared to patients with convalescent KD and to both controls with and controls without fever. Immunohistochemistry demonstrated VEGF and angiopoietin expression in the coronary artery wall in autopsy tissue., Conclusion: Our data support the hypothesis that dysregulation of VEGF and angiopoietins contributes to the disruption of vascular homeostasis in KD., (Copyright © 2012 by the American College of Rheumatology.)

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.

Objective: To investigate whether common genetic variants in the vascular endothelial growth factor (VEGF) gene are associated with Kawasaki disease (KD) and the subsequent development of coronary artery lesions., Methods: Common genetic variants in the VEGF gene were analyzed in an association study in a Dutch cohort of 170 KD patients and 300 healthy Dutch Caucasian controls. Genotyping was done with 5'-nuclease TaqMan assays and 3'-hybridization-triggered fluorescence minor groove binder Eclipse assays., Results: An association with susceptibility to KD was observed with 2 of the 6 single-nucleotide polymorphisms analyzed in VEGF: -2594 A>C (rs699947) and the 236 bp 3' of STP C>T (rs3025039). Also for an 18-bp deletion in the promoter of VEGF a significant difference in the genotype and allele frequencies was observed between the KD patients and the controls. The haplotype CGCC (based on rs699947, rs2010963, rs25648, and rs3025039) was significantly associated with the development of KD (hap score 3.8; P = 0.0002). VEGF plasma levels were significantly higher in patients with the early phase of KD than in the healthy controls, and there was a trend toward higher VEGF plasma levels in KD patients with the -2594 CC and 236 bp 3' of STP CC genotypes., Conclusion: Our results suggest that polymorphisms of the VEGF gene may play a role in the pathogenesis of KD.

Objective: To evaluate the relationship between polymorphisms in the gene coding for mannose-binding lectin (MBL) and the occurrence of coronary artery lesions (CALs) among different age groups of patients with Kawasaki disease., Methods: The frequencies of the genotypes, defined as mutations in codons 52, 54, and 57, and the functional promoter variants of the MBL2 gene were determined in 88 patients with acute Kawasaki disease (median age at onset 1.9 years). The possible influence of the MBL2 genotype on the development and progression of CALs in Kawasaki disease was assessed according to age categories and MBL genotypes in univariate and multivariate analyses., Results: In patients younger than age 1 year, we found an increased risk of developing CALs in the presence of a variant MBL2 genotype (P = 0.008). In contrast, in patients older than age 1 year, we found an increased risk of CALs in those patients with the wild-type genotype (P = 0.005)., Conclusion: Our findings indicate that MBL has an ambiguous role in Kawasaki disease and contributes differently to the pathophysiologic development of CALs, being protective in infants but potentially harmful in patients of older age. The data also imply that the standard treatment of intravenous immunoglobulins to reduce the development of lesions may not be as effective in the very young as it is in the older patients. For the very young, alternative or adjuvant treatment may be indicated, particularly in infants who are MBL-deficient.

We have established an animal model of coronary arteritis which is histopathologically similar to that observed in cases of Kawasaki disease (KD), is a well-known childhood vasculitis syndrome. Coronary arteritis in this mouse model has been induced by intraperitoneal injection of Candida albicans -derived substances (CADS). Arteritis varied by mouse strain with the highest incidence by 71.1% (27/38) found in C3H/HeN mice, but absent in CBA/JN mice (0%, 0/27), suggesting association of genomic background to develop the disease. The present study aims to elucidate the susceptibility loci associated with coronary arteritis by using this animal model. The association of the onset of arteritis with polymorphic microsatellite markers between the two strains was examined using one hundred and fifteen of N1 backcross progeny [(CBAxC3H)F1xC3H]. Based on our analysis, arteritis-susceptibility loci with suggestive linkage were mapped on D1Mit171 and D1Mit245(map position 20.2 cM) on chromosome 1 (P=0.0019). These loci include several kinds of inflammatory cytokine receptors, such as interleukin 1 receptor and tumor necrosis factor receptor. We also found the cytokine response against CADS, levels of inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6 in sera increased within 24 hr after CADS injection. Our results may indicate based on genomics that ligand-receptor interaction between these inflammatory cytokines and the receptors of these cytokines may affect the onset of arteritis.

Aim: To estimate the probability that the parents of patients with Kawasaki disease also had a history of the same disease., Methods: Self-reported parents' histories of Kawasaki disease were collected from data of the 16th nationwide survey of the disease conducted in Japan from January 1999 to December 2000. The incidence of Kawasaki disease was calculated by using data reported in all 16 nationwide surveys and live births in the Japanese vital statistics. The expected number of parents with a history of Kawasaki disease in the general population, which was calculated by using the assumed number of parents in the vital statistics and the incidence of this disease, was compared with the observed number., Results: Among 14,163 parent pairs of patients with Kawasaki disease, 33 parents (25 mothers and 8 fathers) had a history of the disease. The number of parents expected to have a history of Kawasaki disease was 16.1 (8.4 mothers and 7.7 fathers). From a Poisson distribution, the probability of the observed number was less than 0.001 among parents or mothers. The prevalence of a recurrence of Kawasaki disease and incidences involving siblings of patients whose parents had a history of the disease were five or six times higher than those of all patients who were reported in the 16th survey., Conclusion: When compared with parents in the general population, the probability of a history of Kawasaki disease was significantly higher in those parents whose children suffered from the same disease. This suggests that, epidemiologically, a genetic predisposition to Kawasaki disease may be implicated in its occurrence.

Although epidemiologic studies of Kawasaki disease suggest an infectious etiology, the cause of this mysterious disease remains unclear. We describe the occurrence of five episodes of Kawasaki disease over a six-year period in three siblings. Two of the three children experienced recurrent Kawasaki disease and developed coronary artery lesions, which included giant coronary artery aneurysms in the youngest child. The non-contemporaneous occurrence of the disease in these three children emphasizes the importance of a genetic basis and/or environmental factors in the etiology of Kawasaki disease.