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Kawasaki disease (KD) is an autoimmune disease of unknown etiology and has become a main cause of childhood acquired heart disease. KD is more prevalent in males than in females. The reason for this sex bias is unknown. Here, we used whole-exome sequencing (WES) to identify significantly different variants between male and female KD patients. From WES result, a total of 19,500 shared genetic variants in 8421 genes were captured via a series of filters. Further comparisons based on sex were performed to obtain 34 potential sex-biased variants in 34 genes for GO and Reactome Gene Sets enrichment analyses. Moreover, we selected 6 variants associated with immune, cells adhesion, platelet function, homeostasis, and ion channel signaling and expanded the sample size (1247 KD patients containing 713 males and 534 females, 803 healthy population containing 481 males and 322 females) for genotyping validation. From the results, USH2A/rs148135241, LMO7/rs142687160, CEMIP/rs12441101, and EFCC1/rs142391828 presented significant differences of alleles/genotypes frequency distributions between male and female only in KD patients (which were consistent with the result of WES analysis) but not in healthy population. In addition, the result also found that only EFCC1/rs142391828 polymorphism was associated with KD susceptibility. This result suggested that those four variants might play critical roles in sex bias in KD. The study would be in favor of a sex-specific genome atlas establishing and novel sex-specific precision therapies development for KD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children. Activated platelets predispose patients to coronary artery structural lesions that may lead to thrombotic cardiovascular events. To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay of 34 cytokines and discovered thymic stromal lymphopoietin (TSLP) was aberrantly expressed, which remained elevated after intravenous immunoglobulin G (IVIG) treatment and during convalescence in KD patients in comparison to healthy controls. Enzyme-linked immunosorbent assay (ELISA) corroborated the upregulation of TSLP in KD patients, which was exacerbated in convalescent patients complicated with thrombosis. TSLP receptors on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in convalescence KD patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy in healthy blood donors, as observed in KD patients. TSLP, similar to mitophagy agonist carbonyl cyanide 3-chlorophenyl hydrazone (CCCP), promoted thrombosis, which was attenuated by the mitophagy inhibitor Mdivi-1. Co-immunoprecipitation in TSLP-treated platelets revealed TSLP receptor (TSLPR) bound to mitophagy regulators, Parkin and Voltage Dependent Anion Channel Protein 1 (VDAC1).Thus, our results demonstrated that TSLP induced platelet mitophagy via a novel TSLPR/Parkin/VDAC1 pathway that promoted thrombosis in KD. These results suggest TSLP as a novel therapeutic target against KD-associated thrombosis., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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.)

Background: Kawasaki disease (KD) is a systemic vasculitis, and the formation of coronary artery lesions(CAL) is its most common sequela. Both genetic and environmental factors are considered to be important factors of in KD. Integrin α2 (ITGA2) is a transmembrane receptor that is associated with susceptibility to several diseases, but its relevance to KD with CAL is unclear., Methods: We genotyped ITGA2 rs1126643 in 785 KD patients with the CAL and no-CAL(NCAL) (300 patients with CAL, and 485 age- and sex-matched patients with NCAL). OR (95% CI) and adjusted OR (95% CI) were used to evaluate the intensity of the association., Results: We found a significantly increased risk of KD with CAL associated with ITGA2 rs1126643 genotypes (CT vs CC: adjusted OR = 1.57, 95% CI = 1.16-2.12, P = 0.0032; CT/TT vs CC: adjusted OR = 1.49, 95% CI = 1.12-2.00, P = 0.0068; T vs C: adjusted OR = 1.66, 95% CI = 1.16-2.51, P = 0.0165). Moreover, we found that carriers of the CT/TT genotype had a significant risk of KD with coronary artery lesion susceptibility for children ≤60 months of age, and the CT/TT genotype was significantly associated with an increased risk of SCAL formation and MCAL formation when compared with the CC genotype., Conclusion: ITGA2 rs1126643 was associated with increased susceptibility and severity of CAL in KD.

Kawasaki disease (KD) is also called mucocutaneous lymph node syndrome and is an acute febrile pediatric disease characterized by systemic vasculitis. KD typically occurs in children 5 years old or younger and occurs more often in males than in females. miRNA-608 has been reported to interact with interleukin-6 and affect innate immunity. The immune-mediated inflammation could induce the occurrence of KD; however, there is no previous research focused on the relationship between miRNA-608 polymorphism and the KD risk. The present study explored the correlation between the miRNA-608 rs4919510 G>C polymorphism and the risk for KD. We recruited 532 patients with KD and 623 controls to genotype the miRNA-608 rs4919510 G>C polymorphism with a TaqMan allelic discrimination assay. Single-locus analysis showed no significant association between miRNA rs4919510 G>C polymorphism and KD susceptibility. However in an analysis stratified by age, gender, and coronary artery lesion (CAL), we found a relationship between the miRNA-608 rs4919510 G>C polymorphism and KD susceptibility. When KD patients were stratified by coronary injury, the CG/CC genotypes of the miRNA-608 rs4919510 G>C polymorphism contributed to a higher occurrence of KD than that was found in the GG genotype patients (adjusted odds ratio = 0.74, 95% CI = 0.56-0.98, P = 0.033). The present study demonstrated that the miRNA-608 rs4919510 G>C polymorphism may have a CAL-related relationship with KD susceptibility that has not been previously revealed., (© 2019 The Author(s).)

Background: Kawasaki disease (KD) is a systemic form of self-limited vasculitis in children less than five years old, and the main complication is coronary artery injury. However, the etiology of KD remains unclear. The IL-1B polymorphisms rs16944 GG and rs1143627 AA and their diplotype GA/GA have been associated with significantly increased risk of intravenous immunoglobulin (IVIG) resistance in a Taiwanese population, but the relationship between rs16944 A/G and rs1143627 G/A and coronary artery lesions (CALs) in patients with KD has not been investigated. The present study is aimed at investigating whether the rs16944 A/G and rs1143627 G/A polymorphisms in IL-1B were associated with KD susceptibility and CALs in a southern Chinese population., Methods and Results: We recruited 719 patients with KD and 1401 healthy children. Multiplex PCR was used to assess the genotypes of single nucleotide polymorphisms (SNPs), including two SNPs of IL-1B , rs16944 A/G and rs1143627 G/A. According to the results, no significant association was observed between the IL-1B (rs16944 and rs1143627) polymorphisms and KD risk in the patients compared with the healthy controls in our southern Chinese population. However, in further stratified analysis, we found that children younger than 12 months with the rs16944 GG and rs1143627 AA genotypes of IL-1B had a higher risk of CALs than those with the AA/AG genotypes of rs16944 and GG/AG genotypes of rs1143627 (OR = 2.28, 95% CI = 1.32-3.95, P = 0.0032, adjusted OR = 2.33, 95% CI = 1.34-4.04, P = 0.0027)., Conclusions: Our results indicated that there was no association between the rs16944 A/G and rs1143627 G/A gene polymorphisms and KD susceptibility. However, the rs16944 GG and rs1143627 AA genotypes of IL-1B may significantly impact the risk of CAL formation in children younger than 12 months, which may contribute to the pathogenesis of KD. These findings need further validation in multicenter studies with larger sample sizes.

Background: Kawasaki disease (KD) is an acute vasculitis disease that commonly causes acquired heart disease in children. Coronary artery aneurysm (CAA) is a major complication of KD. However, the pathogenesis of KD remains unclear. The results of a genome-wide association study (GWAS) showed that two functional single-nucleotide polymorphisms (SNPs; rs699A>G and rs5050T>G) in the angiotensinogen (AGT) gene were related to cardiovascular disease susceptibility. The purpose of our study was to estimate the relationship between the two GWAS-identified AGT gene polymorphisms and the risk of CAA in Southern Chinese children with KD., Methods: We genotyped the two AGT gene polymorphisms (rs699A>G and rs5050T>G) in 760 KD cases and 972 healthy controls. We used the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the degree of the associations., Results: These two AGT gene polymorphisms were not associated with a risk of KD relative to the controls, but after adjusting for sex and age, the carriers of the rs5050G allele with TG/GG vs TT had an adjusted OR = 1.56, 95% CI = 1.01-2.41, and P = 0.044 relative to the carriers of the rs5050TT genotype. The susceptibility to CAA was more predominant in KD patients younger than 12 months old., Conclusions: Our results indicate that the AGT gene polymorphism rs5050T>G may increase the risk of CAA in children with KD, especially those who are younger than 12 months. These results need to be verified by a validation study with a larger sample size.

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.)

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.)

Kawasaki disease is a multi-system vasculitis and a primary cause of acquired heart disease among children. Genetic factors may increase susceptibility to Kawasaki disease. TBXA2R is a G-protein-coupled receptor that participates in tissue inflammation and is associated with susceptibility to several diseases, but its relevance in Kawasaki disease is unclear. We genotyped TBXA2R (rs1131882 and rs4523) in 694 Kawasaki disease cases and 657 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the intensity of the associations. We found a significantly decreased risk of Kawasaki disease associated with TBXA2R rs4523 G variant genotypes (AG vs AA: adjusted OR = 0.788, 95%CI = 0.626-0.993; GG vs AA: adjusted OR = 0.459, 95%CI = 0.258-0.815; AG/GG vs AA: adjusted OR = 0.744, 95%CI = 0.595-0.929; GG vs AG/AA: adjusted OR = 0.497, 95% CI = 0.281-0.879). In the combined analysis of the two single-nucleotide polymorphisms (SNPs), we found that individuals with two unfavorable genotypes exhibited decreased risk for Kawasaki disease (adjusted OR = 0.754, 95%CI = 0.577-0.985) compared with those who did not have or one unfavorable genotypes. This cumulative effect on protection is effect-genotype dose-dependent (p trend  = 0.022). Moreover, the combined analysis indicated that the two unfavorable genotypes were associated with a decreased risk of Kawasaki disease in children 12-60 months of age, females and the subgroup with non-coronary artery lesion (NCAL) formation compared with those who did not have or one unfavorable genotypes. In conclusion, the TBXA2R rs4523 G allele may contribute to protection against Kawasaki disease and decreased risk of coronary artery aneurysm complications in a southern Chinese population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A previous family-based linkage study revealed that Kawasaki disease (KD) was associated with variations of the ATP-binding cassette subfamily C member 4 (ABCC4) gene in most European populations. However, significant differences exist among ethnic populations in European and Chinese subjects; therefore, whether ABCC4 variants indicate susceptibility to KD in Chinese children is unclear. The purpose of this research was to evaluate correlations between ABCC4 gene polymorphisms and susceptibility to KD in a Southern Chinese population. We genotyped six polymorphisms (rs7986087, rs868853, rs3765534, rs1751034, rs3742106, and rs9561778) in 775 KD patients and 774 healthy controls. Ninety-five percent confidence intervals (95% CIs) and odds ratios (ORs) were used to assess the strength of each association. We found that the rs7986087 T variant genotype was associated with significantly higher susceptibility to KD (adjusted OR = 1.30, 95% CI = 1.05-1.60 for rs7986087 CT/TT). However, the rs868853 T variant genotype was associated with significantly lower susceptibility to KD (adjusted OR = 0.74, 95% CI = 0.59-0.92 for rs868853 CT/CC). Compared with the patients with 0-4 ABCC4 risk genotypes, the patients with 5-6 ABCC4 risk genotypes had a significantly increased risk of KD (adjusted OR = 1.63, 95% CI = 1.07-2.47), and this risk was more significant in the subgroups of females, subjects aged 12-60 months, and individuals with coronary artery lesions. These results indicate that specific single-nucleotide polymorphisms in the ABCC4 gene may increase susceptibility to KD in a Southern Chinese population.

miR-146a plays a critical role in innate immune and inflammatory responses. Kawasaki disease involves immune-mediated inflammatory responses, which leads to vascular endothelial injury. However, there has been no study on the association between the miR-146a rs2910164 C>G polymorphism and Kawasaki disease risk. We enrolled 532 Kawasaki disease patients and 623 healthy controls from southern Chinese population, and the miR-146a rs2910164 C>G polymorphism was genotyped by the TaqMan method. There was no evidence that this polymorphism was associated with Kawasaki disease. Stratified analysis also showed no significant association. The present study indicates that the miR-146a rs2910164 C>G polymorphism may not be associated with Kawasaki disease in the southern Chinese population. Larger multicenter studies are needed to confirm our conclusions., (© 2018 The Author(s).)

Introduction: Kawasaki disease is a kind of systemic vasculitis that mainly damages moderate and small-sized blood vessels, and is a leading cause of coronary artery lesions (CAL). Antiplatelet therapy is a routine component of Kawasaki disease treatment strategies. So it is important to evaluate the antiplatelet effect of aspirin because of the individual biological variability of antiplatelet effect of aspirin. The immature platelet fraction (IPF) has attracted particular attention as it may influence the antiplatelet effect of aspirin. This study investigated the prognostic factors for evaluating the degree of vasculitis and the effect of antiplatelet therapy in children with Kawasaki disease., Materials and Methods: Blood samples were collected from 44 patients with Kawasaki disease before aspirin treatment and 7 to 10 days after treatment. The IPF counts, percentage of the IPF, and highly fluorescent IPF were detected by a Sysmex XE-5000 instrument. The levels of 11-dehydrothromboxane B 2 (11-DH-TXB 2 ), soluble CD40 ligand (sCD40L), and soluble P-selectin (sP-selectin) were measured by ELISA. The correlation between the measured factors and the degree of coronary artery damage in Kawasaki disease was analyzed., Results: We found that 11-DH-TXB 2 , sP-selectin, and sCD40L levels were much more elevated in the CAL group than in the non-coronary artery lesions (NCAL) group before aspirin treatment. The concentrations of 11-DH-TXB 2 , sCD40L, sP-selectin, and IPF were reduced after aspirin treatment in the NCAL group but not the CAL group. This is related to the degree of coronary artery damage in Kawasaki disease patients. Additionally, 11-DH-TXB 2 , sCD40L, sP-selectin, and IPF were positively correlated with the degree of coronary artery damage in Kawasaki disease patients., Conclusion: The current study suggests that the presence of high plasma concentrations of 11-DH-TXB 2 , sCD40L, sP-selectin, and IPF can be considered a risk factor and experimental biomarker for CAL in Kawasaki disease patients., Competing Interests: Disclosure The authors report no conflicts of interest.