The Network of Pro-Inflammatory Factors CD147, DcR3, and IL33 in the Development of Kawasaki Disease.

INTRODUCTION: Kawasaki disease (KD) is an acute febrile systemic vasculitis, but the etiology remains unknown. We studied serum levels of CD147, DcR3, and IL33 in different stages of KD to explore the value of CD147, DcR3, and IL33 in the pathophysiology of KD. METHODS: We measured serum levels of CD147, DcR3, and IL33 by enzyme-linked immunosorbent assay (ELISA) at different stages with 71 KD patients and 66 healthy control children. We apply for network tools GeneMANIA and Cytoscape APP to analyze the functions of these pro-inflammatory factors at the gene and protein level. RESULTS: Serum levels of CD147, DcR3, and IL33 were significantly increased in KD patients before IVIG treatment. Serum levels of CD147, DcR3, and IL33 gradually decreased over time after the treatment of IVIG. Eight cases were IVIG non-responders, while nine KD patients got CALs, but they did not overlap. And there were no statistical differences between group IVIG responders and IVIG non-responders or between groups without CALs and with CALs. We explored the functions of CD147, DcR3, and IL33 from GeneMANIA and Cytoscape APP and found these third pro-inflammatory factors were coexpressed, physical interactions, genetic interactions with other KD-related factors. CONCLUSION: CD147, DcR3, and IL33 are involved in the pathophysiology of KD, which provides novel evidence for diagnosing and treating KD with their inhibitors.

Systematic confirmation study of GWAS-identified genetic variants for Kawasaki disease in a Chinese population.

Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) associated with Kawasaki disease (KD). In this study, we replicated the associations of 10 GWAS-identified SNPs with KD in a Han Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression, and cumulative effect of non-risk genotypes were also performed. Although none of the SNPs reached the corrected significance level, 4 SNPs showed nominal associations with KD risk. Compared with their respective wild type counterparts, rs1801274 AG+GG genotypes and rs3818298 TC+CC genotypes were nominally associated with the reduced risk of KD (OR = 0.77, 95% CI = 0.59-0.99, P = 0.045; OR = 0.74, 95% CI = 0.56-0.98, P = 0.038). Meanwhile, rs1801274 GG genotype, rs2736340 CC genotype or rs4813003 TT genotype showed a reduced risk trend (OR = 0.57, 95% CI = 0.35-0.93, P = 0.024; OR = 0.46, 95% CI = 0.26-0.83, P = 0.010; OR = 0.64, 95% CI = 0.43-0.94, P = 0.022), compared with rs1801274 AG+AA genotypes, rs2736340 CT+TT genotypes or rs4813003 TC+CC genotypes, respectively. Furthermore, a cumulative effect was observed with the ORs being gradually decreased with the increasing accumulative number of non-risk genotypes (Ptrend<0.001). In conclusion, our study suggests that 4 GWAS-identified SNPs, rs2736340, rs4813003, rs3818298 and rs1801274, were nominally associated with KD risk in a Han Chinese population individually and jointly.

A genetic variant rs1801274 in FCGR2A as a potential risk marker for Kawasaki disease: a case-control study and meta-analysis.

OBJECTIVES: Recent genome-wide association study found rs1801274, a functional single nucleotide polymorphism (SNP) in IgG receptor gene FCGR2A, was associated with increased risk of Kawasaki disease (KD). However, subsequent studies on the role of this SNP were limited and controversial. METHODS: A case-control study was conducted in a Chinese Han population including 428 KD patients and 493 controls to examine the association between rs1801274 and KD susceptibility. A meta-analysis was performed in combination with the relevant published studies to further clarify such an association. RESULTS: Our case-control study found that rs1801274 was significantly associated with increased risk of KD in the Chinese Han population, with an odds ratio (OR) of 1.58 (95% CI = 0.96-2.62) for the GA genotype and 1.93 (95% CI = 1.16-3.19) for the AA genotype compared with the GG genotype. The result of meta-analysis further demonstrated that the A allele of rs1801274 was significantly correlated with KD risk under the allelic model (OR = 1.35, 95% CI = 1.27-1.44) without heterogeneity by fixed-effects model analysis (Q = 17.30, p = 0.139). Moreover, sensitivity analysis supported the robustness of this meta-analysis. CONCLUSION: These results further confirm that rs1801274 in the FCGR2A gene is significantly associated with increased risk of KD.

The roles of Ca2+/NFAT signaling genes in Kawasaki disease: single- and multiple-risk genetic variants.

Ca(2+)/nuclear factor of activated T-cells (Ca(2+)/NFAT) signaling pathway may play a crucial role in Kawasaki disease (KD). We investigated 16 genetic variants, selected by bioinformatics analyses or previous studies, in 7 key genes involved in this pathway in a Chinese population. We observed a significantly or marginally increased KD risk associated with rs2720378 GC + CC genotypes (OR = 1.39, 95% CI = 1.07-1.80, P = 0.014) or rs2069762 AC + CC genotypes (OR = 1.28, 95% CI = 0.98-1.67, P = 0.066), compared with their wild type counterparts. In classification and regression tree analysis, individuals carrying the combined genotypes of rs2720378 GC or CC genotype, rs2069762 CA or CC genotype and rs1561876 AA genotype exhibited the highest KD risk (OR = 2.12, 95% CI = 1.46-3.07, P < 0.001), compared with the lowest risk carriers of rs2720378 GG genotype. Moreover, a significant dose effect was observed among these three variants (Ptrend < 0.001). In conclusion, this study implicates that single- and multiple-risk genetic variants in this pathway might contribute to KD susceptibility. Further studies on more comprehensive single nucleotide polymorphisms, different ethnicities and larger sample sizes are warranted, and the exact biological mechanisms need to be further clarified.

8p22-23-rs2254546 as a susceptibility locus for Kawasaki disease: a case-control study and a meta-analysis.

8p22-23-rs2254546 was firstly discovered to be associated with Kawasaki disease (KD) susceptibility by a genome-wide association study. However, only one Chinese replication study has been performed so far. To verify this association in another Chinese population, a hospital-based case-control study in Zhejiang province was conducted followed by an integrated meta-analysis, comprising five case-control studies of 1958 cases, 5615 controls and four transmission disequilibrium tests of 503 trios. In our case-control study, significant associations were observed between GG genotype or GG/GA genotypes of rs2254546 and increased KD risk (OR = 1.86, 95% CI = 1.01-3.41, P = 0.045; OR = 1.83, 95% CI = 1.01-3.33, P = 0.048), compared with AA genotype; however, no significant association was found in allelic model (OR = 1.20, 95% CI = 0.96-1.50, P = 0.117). The meta-analysis further revealed that the G allele was significantly associated with the increased KD risk without evidence of heterogeneity (OR = 1.55, 95% CI = 1.42-1.70, P < 0.001). In conclusion, rs2254546 polymorphism might significantly contribute to the risk of KD.

Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease.

OBJECTIVE: To investigate the roles of serum Th1 and Th2 cytokines in Kawasaki disease (KD) and determine whether the Th1/Th2 cytokine profiles in children with KD may be involved in intravenous immunoglobulin (IVIG) resistance and development of coronary artery lesions (CALs). METHODS: Serum Th1 and Th2 cytokines, including interferon-γ (IFNγ), tumor necrosis factor α (TNFα), interleukin-10 (IL-10), IL-6, IL-4, and IL-2, were measured using a cytometric bead array in the serum of 143 patients with KD before and after treatment with IVIG (pre-IVIG, at 3 days after temperature normalization following IVIG treatment [post-IVIG], and 1 month posttreatment). RESULTS: Levels of IL-6, IL-10, TNFα, and IFNγ were significantly increased in KD patients pre-IVIG. Post-IVIG, the levels of IL-6, IL-10, and IFNγ quickly decreased. The levels of TNFα decreased significantly after IVIG treatment in KD patients without CALs post-IVIG and in KD patients who were IVIG responders, but increased slightly in KD patients with CALs post-IVIG and in KD patients who were IVIG nonresponders. Before IVIG treatment, the levels of IL-4, IL-6, IL-10, and IFNγ were significantly higher in KD patients with CALs than in those without CALs. The post-IVIG levels of IL-6 and IL-10 were significantly higher in IVIG nonresponders than in IVIG responders. Pre-IVIG, an IL-10 level >8 pg/ml had a sensitivity of 75.0% and a specificity of 64.4% for predicting CALs, while a TNFα level <2 pg/ml had a sensitivity of 66.7% and a specificity of 74.2% for predicting IVIG resistance. Post-IVIG, an IL-6 level >10 pg/ml had a sensitivity of 67.9% and a specificity of 81.7% for predicting CALs, while an IL-10 level >6 pg/ml had a sensitivity of 53.6% and a specificity of 86% for predicting CALs. CONCLUSION: Determination of the serum Th1/Th2 cytokine profile may be helpful for predicting the disease prognosis and targeting treatment strategies in patients with KD.

[Six Kawasaki disease patients with acute coronary artery thrombosis].

OBJECTIVE: To improve the awareness of acute coronary artery thrombosis in Kawasaki disease (KD). METHOD: Six KD patients with acute coronary artery thrombosis (Jan. 2004 to Jan. 2013) were studied retrospectively. The basic information, clinical manifestations, laboratory data, echocardiography and electrocardiography (ECG), method and consequence of thrombolytic therapy were analyzed. RESULT: The mean age of patients with coronary artery thrombosis (5 males and 1 female) was (17.2 ± 11.3) months.Five cases had thrombosis in left coronary artery (LCA), and four cases had thrombosis in aneurysm of left anterior descending artery (LAD). One case had thrombosis in both left and right coronary artery (RCA).One case died. Maximum thrombus was about 1.60 cm × 0.80 cm, locating in LAD. The diameter of LCA and RCA was (0.44 ± 0.07) cm and (0.45 ± 0.07) cm. Two patients showed abnormal ECG. Case 3 showed ST segment depression in lead V5. Case 6 showed myocardial infarction.In acute phase of KD, three patients received treatment with intravenous immunoglobin (IVIG), five patients were treated with aspirin.In sub-acute and convalescent phase of KD, all patients were treated with low-dose aspirin.Warfarin and dipyridamole were applied in 5 patients. All cases were treated with thrombolytic therapy using urokinase and/or heparin. After thrombolytic therapy, echocardiography showed thrombolysis in four cases and no change in one.One patient died of myocardial infarction. CONCLUSION: Most of acute coronary thrombosis in KD occurred in LAD. KD patients with coronary artery thrombosis are at risk of sudden death due to myocardial infarction.

Reverse regulation of soluble receptor for advanced glycation end products and proinflammatory factor resistin and S100A12 in Kawasaki disease.

INTRODUCTION: Kawasaki disease (KD), an acute febrile disease, characterized by systemic vasculitis, predominantly affects infants and children under 5 years of age. Coronary artery lesions (CALs) are its most critical complication, and the etiology remains unknown yet. In order to explore the value of resistin, S100A12 and soluble receptor for advanced glycation end products (sRAGE) in the pathophysiology of KD, we studied the serum levels of resistin, S100A12 and sRAGE in different stages of KD. METHODS: Serum levels of resistin, S100A12 and sRAGE were measured by enzyme-linked immunosorbent assay (ELISA) method in 15 healthy children and 40 KD patients at acute, afebrile and subacute stage. RESULTS: The resistin and S100A12 levels, including the ratio of resistin to sRAGE and S100A12 to sRAGE increased significantly in the acute stage, and decreased progressively in the afebrile and subacute stage. However, the sRAGE levels decreased significantly in the acute stage, and increased progressively in the afebrile and subacute stage. In the acute, afebrile and subacute stage, the resistin levels were higher in intravenous immunoglobulin (IVIG) non-responders (0.64 ± 0.30, 0.48 ± 0.35, 0.28 ± 0.19, × 102 ng/ml) than in IVIG responders (0.35 ± 0.24, 0.21 ± 0.19, 0.12 ± 0.05, × 102 ng/ml). In the acute and subacute stage, the S100A12 levels were higher in IVIG non-responders (7.92 ± 2.61, 4.98 ± 4.75, × 102 ng/ml) than in IVIG responders (5.05 ± 3.22, 2.35 ± 2.26, × 102 ng/ml). In the afebrile and subacute stage, the sRAGE levels were lower in IVIG non-responders (3.51 ± 2.64, 3.65 ± 3.27, × 102 pg/ml) than in IVIG responders (6.00 ± 2.78, 7.19 ± 2.88, × 102 pg/ml). The resistin levels were positively correlated with S100A12 levels. The sRAGE levels were negatively related with S100A12 and resistin levels. CONCLUSIONS: Resistin, S100A12 and sRAGE are involved in the pathophysiology of KD.

Cardiogenic shock: do not forget the possibility of Kawasaki disease.

We report the case of a six-year-old boy who presented with cardiogenic shock due to Kawasaki disease (KD). He was misdiagnosed at first as septic shock. After careful examination, he was diagnosed as KD complicated with acute coronary syndrome, which leads to cardiogenic shock. Cardiogenic shock is often neglected as a complication of KD, and it tends to be misdiagnosed. We hereby call attention to KD, in some cases of which, it can lead to acute coronary syndrome in the acute phase.