Kawasaki Disease Susceptibility Research Articles

Frequencies of Human Leukocyte Antigen Alleles in Turkish Children with Kawasaki Disease

Abstract Objective Kawasaki disease (KD) is an acute systemic vasculitis that is one of the major causes of acquired heart disease especially in young children. The pathogenesis of KD is still unclear. The increased incidence of the disease among Japanese children and siblings of affected patients suggests a genetic component to KD susceptibility. Several reports have studied human leukocyte antigen (HLA) polymorphisms in different populations with KD and found various results. In the present study, we aimed to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in Turkish children with KD. Methods The study was conducted between January 2016 and February 2018. HLA Class I (A, B, and C) and Class II (DRB1 and DQB1) alleles of patients and healthy controls were studied using the low-resolution DNA-based sequence-specific oligonucleotide method. Results Fifty children with KD and 500 healthy controls were included in this study. In the analysis of HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles, no statistical difference was found in the frequency of alleles between the patients with KD and the control group. However, a significantly lower frequency of the HLA-DQB1*03 allele was observed in the KD group than in the control group (p < 0.001, odds ratio [OR]: 0.29, 95% confidence interval [CI]: 0.15–0.55). When the patients with KD were divided into two subgroups with or without coronary artery lesions (CALs), the frequency of the HLA-DQB1*03 allele was also found lower in the KD group with CALs than the KD group without CALs (p = 0.008, OR: 0.19, 95% CI: 0.05–0.68). Conclusion The study may guide future studies on HLA-DQB1*03 whether it is a protective allele for KD and CALs in Turkish children.

FCGR2/3 polymorphisms are associated with susceptibility to Kawasaki disease but do not predict intravenous immunoglobulin resistance and coronary artery aneurysms.

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 (FcγRs), 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. 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. 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. 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.

Whole-exome sequencing reveals Kawasaki disease susceptibility genes and their association with coronary artery lesion.

This study aimed to explore Kawasaki disease (KD) susceptibility genes and their complications like coronary artery lesions (CAL) using whole exome sequencing (WES). Between April 1, 2021, and December 31, 2022, our study included 55 pediatric patients diagnosed KD at our center, alongside a cohort of healthy children who sought medical care at our institution during the same timeframe. We extracted peripheral blood DNA from all participants and employed the advanced high-throughput Illumina Next-Generation Sequencing technology for comprehensive analysis. Through bioinformatics evaluation, we identified potential susceptibility genes. Moreover, from the 55 KD patients, we selected 15 for the CAL group and 40 for the non-CAL group. We aimed to investigate whether there were significant differences in the allele frequencies of the targeted susceptibility genes between these subgroups, to explore the risk alleles associated with the development of CAL in KD. HLA-DRB1 rs17882084 and IL6ST rs781455079 genotypes and alleles differed significantly between KD and non-KD (P < 0.05). No differences existed for IL17RC rs143781415 and VEGFB rs776229557 (P > 0.05). No differences in HLA-DRB1 rs17882084, IL6ST rs781455079, and VEGFB rs776229557 genotypes existed between CAL and non-CAL groups (P > 0.05). However, the IL17RC rs143781415 genotype differed significantly between them (P < 0.05). HLA-DRB1 rs17882084 and IL6ST rs781455079 genotypes may be potential KD susceptibility gene candidates. Specifically, HLA-DRB1 rs17882084 GA genotype and A allele, and IL6ST rs781455079 TC genotype and C allele may increase KD risk. Additionally, the IL17RC rs143781415 genotype may increase CAL risk in KD patients.

Exaggerated Kawasaki disease-associated vasculitis in C-C Motif Chemokine Receptor 5 (CCR5) deficient mice is driven by Granulocyte Colony Stimulating Factor (G-CSF) overproduction and neutrophil formation and infiltration

Kawasaki disease (KD) is a rare but serious illness that primarily affects children. It is characterized by inflammation of the blood vessels throughout the body, including the coronary arteries (CA). Polymorphisms in CCR5 influence KD susceptibility and cardiovascular outcome, but the mechanisms are enigmatic yet. Thus, we aimed to explore the mechanisms by which polymorphisms in CCR5 aggravate the vascular injury in KD by using the Candida albicans water soluble (CAWS) fraction model. Male (6-10-weeks-old) CCR5 deficient mice (CCR5−/−) and their counterpart (CCR5+/+) were used. Cardiac single-cell transcriptomics (scRNAseq) analysis of both control and KD mice revealed an inflammatory landscape characterized by an abundance of macrophages, monocytes, and neutrophils. Additionally, our scRNAseq data indicated that CCR5 expression is predominantly observed in macrophages and monocytes in KD mice, whereas its ligands, CCL3 and CCL4, are primarily expressed in neutrophils. Our CellChat analysis uncovered robust intercommunication between neutrophils and macrophages and monocytes. This interaction involves the production of CCL3 and CCL4 by neutrophils, which act on CCR5 receptors in macrophages and monocytes. To validate this scRNAseq data, we analyzed the vasculitis levels in CA and immune cells content in CCR5+/+ and CCR5−/− mice with KD via histology and flow cytometry. CCR5−/− mice with KD exhibited aggravated vasculitis, increased neutrophil accumulation [(% in relation to 10^6 leukocytes) CCR5+/+: 2.5±1.7 n=4 vs. CCR5+/+ KD: 16.1±3.2 n=4], and CCR5−/− KD: 30.2±7.4 n=4), alongside cardiac senescence (3-fold rise in p21 expression) and a 2-fold increase in Caspase-3, indicating increased cell death compared to CCR5+/+ with KD. Mechanistically, our plasma proteome profile cytokine assay revealed that KD increases circulating IL-6 and circulating neutrophil, interestingly CCR5−/− mice with KD showed further circulating IL-6 and neutrophil along with G-CSF, which plays a critical role in stimulating the production and release of granulocytes, particularly neutrophils, from the bone marrow into the bloodstream. Thus, deficiency in CCR5 triggers a worse vasculitis in KD by regulating an over production of neutrophil by bone marrow via G-CSF, which in turn will lead to an exaggerated IL-6 production, further accumulation in CA, and aggravated cardiac damage. FAPESP (2022/06639-2), NHLBI-R00 (R00HL14013903), AHA (CDA857268 and 23DIVSUP1069230), Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania Vitalant, and Children's Hospital of Pittsburgh of the UPMC Health System. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Susceptibility of TSPAN5 polymorphisms to Kawasaki disease and immunoglobulin therapy resistance in southern Chinese children

Kawasaki disease (KD) is a condition characterized by acute multi-system vasculitis and high fever in infants and children. Intravenous immunoglobulin (IVIG) is the established therapeutic approach of KD,foralleviating inflammation and mitigate the risk of arterial wall dilation and the development of coronary artery aneurysms (CAA). But almost 20% of the patients developed resistance to IVIG and displayed persistent fever after standard primary treatment. TSPAN5, belonging to the Tetraspanin family, has been demonstrated to modulate innate immunity in a range of human diseases. It accomplishes this by engaging with integrins and actively participating in the process of infection recognition. However, its relevance to susceptibility and IVIG therapy response of KD was unexposed. In the present study, our Integrative analysis of KD transcriptomic data and GTEx data revealed that the eQTL rs12504972 might modify the downregulation of TSPAN5 in KD patients. Moreover, our findings suggest a potential association between TSPAN5/rs12504972 and an elevated susceptibility as well as IVIG resistance among patients with Kawasaki disease in southern China. The results provided a new insight that TSPAN5 triggered KD susceptibility and resistance of IVIG therapy on the genomic level.

Risk factors for coronary artery abnormalities and resistance to immunoglobulin plus ciclosporin A therapy in severe Kawasaki disease: subanalysis of the KAICA trial, randomized trial for cicrosporin A as the first-line treatment.

To investigate risk factors for coronary arterial abnormalities (CAAs) and resistance to treatment in patients with Kawasaki disease (KD) receiving intravenous immunoglobulin (IVIG) plus ciclosporin A (CsA) as the first-line treatment, we performed a subanalysis of baseline data of participants in the KAICA trial, a phase 3, randomized study (JMA-ILA00174). All data of the patients enrolled in the KAICA trial, who had a Gunma score ≥5 at diagnosis and had been randomly assigned to either IVIG (2 g/kg/24 h) plus CsA (5 mg/kg/day for 5 days) (n = 86) or IVIG alone (n = 87), were subjected to this study. CAA was defined by a Z score ≥2.5 observed within 4 weeks after treatment initiation. Baseline data including genotypes of KD susceptibility genes were compared between subgroups of patients for CAA or treatment response for each treatment group. Backword-forward stepwise logistic regression analyses were performed. Pre-Z-max, defined as the maximum among Z scores on four coronary artery branches before treatment, was higher in patients with CAA in both treatment groups and was associated with CAA in IVIG plus CsA treatment group [odds ratio (OR) = 17.0]. High serum total bilirubin level was relevant to treatment resistance only in the IVIG plus CsA group (OR = 2.34). Coronary artery enlargement before treatment is a major determinant of CAA even in KD patients treated with initial IVIG treatment intensified by addition of CsA. Baseline serum total bilirubin level was a risk factor associated with resistance to IVIG plus CsA.

Abstract P178: Role Of The C-C Motif Chemokine Receptor 5 (CCR5) Polymorphism In A Mouse Model Of Kawasaki Disease-Induced Vasculitis

Introduction: Kawasaki disease (KD) is the most common form of vasculitis in young children. However, the etiology and the vulnerability of vasculitis are still enigmatic. In children, polymorphisms in CCR5 influence KD susceptibility and cardiovascular outcome, but the mechanisms are unclear. Therefore, the use of murine models is an attractive strategy to evaluate the interface between immune system and vasculitis in KD. We aimed to explore the mechanisms by which polymorphisms in CCR5 aggravates the vascular injury in KD by using the Candida albicans water soluble (CAWS) fraction model. Methods: Male (6-10-weeks-old) CCR5 deficient mice (CCR5 -/- ) and their counterpart (CCR5 +/+ ) were used. Results: After 28 days of CAWS treatment, CCL5 and CCR5 levels were increased in plasma [(pg/mL) CCR5 +/+ : 5.01 ± 0.7 n=5 vs . CCR5 +/+ CAWS: 18.71 ± 1.4* n=4, *p&lt;0.05], and heart (14-fold changes) of CCR5 +/+ , which was associated with a clear vasculitis in coronary and AA, as well as cardiac senescence (p21 expression), cell death (caspase-3 levels), and higher contractility to norepinephrine (NA) in AA [(mN) CCR5 +/+ : 3.60 ± 0.3 n=4 vs . CCR5 +/+ CAWS: 5.72 ± 0.2* n=4, *p&lt;0.05]. Remarkably, CCR5 -/- displayed a worse vasculitis level, further accumulation of cardiac p21 and caspase-3, and an exacerbated vascular response to NA (CCR5 -/- -CAWS: 6.70 ± 0.4 # n=5, # p&lt;0.05 vs . CCR5 +/+ CAWS). To understand the mechanisms, we performed a plasma proteome profile cytokine assay, which revealed that KD elevates the levels of various inflammatory mediators (IL-1β, IL-6, IL-17, and TNFα) and chemokines (CXCL2, 10, 11, 19, 12, and 13 and CCL2, 3, and 4), which were exacerbated in CCR5 -/- . Yet, CAWS induced an increase in cardiac neutrophil infiltration in CCR5 +/+ [(% in relation to 10 ^ 6 leukocytes) CCR5 +/+ : 2.5 ± 1.7 n=4 vs . CCR5 +/+ CAWS: 16.1 ± 3.2* n=4, *p&lt;0.05], which was worsened in CCR5 -/- (CCR5 -/- -CAWS: 30.2 ± 7.4 # n=4, # p&lt;0.05 vs . CCR5 +/+ CAWS). Conclusion: Deficiency in CCR5 aggravates the vasculitis levels and cardiovascular outcomes likely regulating neutrophil infiltration and cytokines production. Therefore, children with polymorphism in CCR5 might be more susceptible in developing a severe vasculitis during KD.

Whole-exome sequencing analysis identifies novel variants associated with Kawasaki disease susceptibility

BackgroundKawasaki disease (KD) is an acute pediatric vasculitis affecting genetically susceptible infants and children. Although the pathogenesis of KD remains unclear, growing evidence links genetic susceptibility to the disease.MethodsTo explore the genes associated with susceptibility in KD, we applied whole-exome sequencing to KD and control subjects from Yunnan province, China. We conducted association study analysis on the two groups.ResultsIn this study, we successfully identified 11 significant rare variants in two genes (MYH14 and RBP3) through the genotype/allele frequency analysis. A heterozygous variant (c.2650G > A, p.V884M) of the RBP3 gene was identified in 12 KD cases, while eight heterozygous variants (c.566G > A, p.R189H; c.1109 C > T, p.S370L; c.3917T > G, p.L1306R; c.4301G > A, p.R1434Q; c.5026 C > T, p.R1676W; c.5329 C > T, p.R1777C; c.5393 C > A, p.A1798D and c.5476 C > T, p.R1826C) of the MYH14 gene were identified in 8 KD cases respectively.ConclusionThis study suggested that nine variants in MYH14 and RBP3 gene may be associated with KD susceptibility in the population from Yunnan province.

Whole-Exome Sequencing for Identification of Potential Sex-Biased Variants in Kawasaki Disease Patients.

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.

Identification of B-cell-related HSPG2 and CDSN as susceptibility loci for Kawasaki disease

Kawasaki disease (KD) is an acute pediatric vasculitis that predominantly affects children under the age of 5 years. To date, genome-wide association studies (GWAS) have identified several KD susceptibility genes (e.g., BLK, CD40, FCGR2A, BCL2L11, and IGHV), which are mainly involved in B cell immunity. In this study, we aimed to identify additional KD susceptibility genes mainly involved in B cell development and functions by analyzing our previous GWAS data and conducting a replication study using new sample. Initially, we selected 30 single nucleotide polymorphisms (SNPs) in B-cell-related genes that were significantly (P < 0.01) associated with KD in our previous GWAS analysis of 247 KD cases with complete type and 1,000 healthy controls. Replication study was performed by genotyping the new 837 KD case samples with Fluidigm system and comparing them with 3,553 control genotypes. Among the 30 candidate SNPs, two were significantly associated with KD (P < 0.001) in the replication study. An even greater association between these SNPs and KD was observed in the combined analysis of GWAS and replication samples: odds ratio (OR) = 1.97 (P = 8.61 × 10−6) for rs2270699 (nonsynonymous SNP: c.10588C > T, p.Arg3530Trp) in the heparan sulfate proteoglycan 2 (HSPG2) gene and OR = 1.28 (P = 1.34 × 10−6) for rs3130992 (intronic SNP) in both the corneodesmosin (CDSN) and psoriasis susceptibility 1 candidate 1 (PSORS1C1) genes. These results suggest that the B-cell-related genes, HSPG2 and CDSN or PSORS1C1, play a role in the development of KD.

A LncRNA gene polymorphism (rs1814343) is associated with the risk of coronary artery lesions in southern Chinese Kawasaki disease patients.

Kawasaki disease (KD) is a multisystemic angiitis, and its most disastrous complication is coronary artery lesions (CALs). Recently, the role of long non-coding RNAs (lncRNAs) in KD has been reported. rs1814343 is a lncRNA, but the relationship between the lncRNA rs1814343 polymorphism and KD risk remains elusive. We enrolled 1625 Kawasaki disease patients (583 patients with CAL and 1042 without CAL) and 1000 healthy controls from a southern Chinese population. We genotyped the rs1814343 C > T polymorphism in KD and control patients using the TaqMan method. The odds ratio (OR) and 95% confidence interval (CI) were used to estimate the strength of the association. There was no significant association between the lncRNA rs1814343 C > T polymorphism and KD susceptibility. However, we stratified patients in this study by CAL and sex. First, compared with the control groups, we found that the rs1814343 genotype increased risk for KD patients with CAL (TT vs. CC + CT: OR = 1.36, 95% CI = 1.08-1.71, p = 0.009). Moreover, when KD patients were stratified by CAL, the TT genotypes of this lncRNA polymorphism contributed to a relatively higher occurrence of KD with CAL than that was found in the CC/CT genotype patients (TT vs. CC + CT: OR = 1.35, 95% CI = 1.07-1.69, p = 0.011). In addition, our research suggested that the TT variant genotype in the lncRNA rs1814343 had an obvious risk of KD with CAL susceptibility in male children. The lncRNA rs1814343 C > T polymorphism was related to higher susceptibility of KD with CAL.

Association study of miR-149, miR-196a2, and miR-499a polymorphisms with coronary artery aneurysm of Kawasaki disease in southern Chinese population.

BackgroundAccumulating 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.MethodsWe 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).ResultsWe 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.ConclusionsOur 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.

Association of ITPKC gene polymorphisms rs28493229 and rs2290692 in North Indian children with Kawasaki disease.

Single-nucleotide polymorphisms (SNPs) of several genes are linked to the etiopathogenesis of Kawasaki disease (KD). Association of SNPs of inositol 1,4,5-triphosphate-3-kinase C (ITPKC) gene with susceptibility to KD and coronary artery lesions (CALs) has been observed in children of certain ethnicities, but not from others. The present study was planned to explore this genetic association in the North Indian cohort. Fifty children with KD and 50 age- and sex-matched controls were studied for two SNPs (rs28493229 and rs2290692) of the ITPKC gene using polymerase chain reaction and restriction fragment length polymorphism. Findings were confirmed by Sanger sequencing. A meta-analysis was also carried out for GG and CC genotypes of the SNPs. There was significant association between KD susceptibility and CG + GG genotype of rs2290692 (p = 0.015, odds ratio = 4.1, 95% confidence interval = 1.38-13.83). None of the single alleles or genotypes of the SNPs of ITPKC were, however, significantly associated with KD susceptibility. A meta-analysis also did not show any significant association of these SNPs to KD susceptibility. Our findings suggest that ITPKC gene SNPs (rs28493229 and rs2290692) did not have a significant association with susceptibility to KD in children from North India. Larger multicentric studies incorporating different ethnicities are required to understand the genetic basis of KD. While SNP rs28493229 of the ITPKC gene is not found to be associated with susceptibility to KD, the combined genotype of SNP rs2290692 is shown to be associated. Impact of ITPKC gene SNP on KD is different across different races and ethnicities. We could find an association of the combined genotype of rs2290692 with it in the Indian population. This study highlights that phenotype and genotypic association of KD varies with ethnicities. Larger multicentric studies are required to reach a conclusion regarding the genetic association of KD.

Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development.

Kawasaki disease (KD) is an acute systemic vasculitis that occurs predominantly in children under 5 years of age. Despite much study, the etiology of KD remains unknown. However, epidemiological and immunological data support the hygiene hypothesis as a possible etiology. It is thought that more sterile or clean modern living environments due to increased use of sanitizing agents, antibiotics, and formula feeding result in a lack of immunological challenges, leading to defective or dysregulated B cell development, accompanied by low IgG and high IgE levels. A lack of B cell immunity may increase sensitivity to unknown environmental triggers that are nonpathogenic in healthy individuals. Genetic studies of KD show that all of the KD susceptibility genes identified by genome-wide association studies are involved in B cell development and function, particularly in early B cell development (from the pro-B to pre-B cell stage). The fact that intravenous immunoglobulin is an effective therapy for KD supports this hypothesis. In this review, I discuss clinical, epidemiological, immunological, and genetic studies showing that the etiopathogenesis of KD in infants and toddlers can be explained by the hygiene hypothesis, and particularly by defects or dysregulation during early B cell development.

Single-Nucleotide Polymorphism LncRNA AC008392.1/rs7248320 in CARD8 is Associated with Kawasaki Disease Susceptibility in the Han Chinese Population.

BackgroundKawasaki disease (KD) is a multisystem vasculitis in infants and young children and involved in the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation. Genetic factors may increase the risk of KD. To assess the association between rs7248320 in long noncoding RNA (lncRNA) AC008392.1 located in the upstream region of CARD8 and the risk of KD, a case–control study was conducted in the Han Chinese population.MethodsThis study genotyped the polymorphism rs7248320 in the lncRNA AC008392.1 gene using the TaqMan real-time polymerase chain reaction assay. The genetic contribution of rs7248320 was evaluated using odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. The association between rs7248320 and KD susceptibility was analyzed by performing a hospital-based case–control study including 559 KD patients and 1055 non-KD controls.ResultsIn this study, a significant relationship between rs7248320 and KD risk was observed in the genotype/allele frequency distribution. The rs7248320 polymorphism was associated with a significantly decreased risk of KD after adjustment for age and sex (AG vs AA: adjusted OR = 0.80, 95% CI: 0.64–0.99, P = 0.0421; GG vs AA: adjusted OR = 0.71, 95% CI: 0.51–1.00, P = 0.0492; AG/GG vs AA: adjusted OR = 0.78, 95% CI: 0.63–0.96, P = 0.0186). Moreover, the rs7248320 G allele also exhibited a decreased risk for KD (adjusted OR = 0.83, 95% CI: 0.72–0.97, P = 0.0193) compared with the A allele. In the stratification analysis, compared to the rs7248320 AA genotype, AG/GG genotypes were more protective for males (OR = 0.71, 95% CI: 0.55–0.93, P = 0.0122).ConclusionThis study suggests for the first time that the lncRNA AC008392.1 rs7248320 polymorphism may be involved in KD susceptibility in the Han Chinese population.

Protective Effect of TNFRSF11A rs7239667 G > C Gene Polymorphism on Coronary Outcome of Kawasaki Disease in Southern Chinese Population.

BackgroundThe main symptoms of Kawasaki disease (KD) are inflammatory vasculitis characterized by fever lasting 1–2 weeks, failure to respond to antibiotic treatment, conjunctivitis, redness of the lips and mouth, strawberry tongue, and painless enlargement of the neck lymph nodes. Studies have been shown that tumor necrosis factor (TNF) and TNF receptor family members are abnormally expressed in the acute phase of Kawasaki disease, also revealing that these two play a significant role in the pathogenesis of KD. The purpose of our study is to determine the relationship between TNFRSF11A rs7239667 and the pathogenesis of KD and Coronary artery lesions in KD.Methods and ResultsIn this study, TNFRSF11A (rs7239667) genotyping was performed in 1396 patients with KD and 1673 healthy controls. Our results showed that G > C polymorphism of TNFRSF11A (rs7239667) was not associated with KD susceptibility. In addition, the patients with KD were divided into CAA and NCAA groups according to whether they had coronary artery aneurysm (CAA) or not, and the TNFRSF11A rs7239667 genotyping was performed in the two groups. After gender and age calibration, We found that genotype CC of TNFRSF11A may be a protective factor in KD coronary artery damage (adjusted OR = 0.69 95% CI = 0.49–0.99 P = 0.0429) and is more significant in children with KD ≤ 60 months (adjusted OR = 0.49 95% CI = 0.49–0.93 P = 0.0173).ConclusionOur study suggests that TNFRSF11A rs7239667 G > C polymorphism maybe play a protective gene role for the severity of KD coronary artery injury and is related to age, which has not been previously revealed.

Innate immune response analysis in COVID-19 and kawasaki disease reveals MIS-C predictors

Background/purposeThe association between dysregulated innate immune responses seen in Kawasaki disease (KD) with predisposition to Kawasaki-like multisystem inflammatory syndrome in children (MIS-C) remains unclear. We aimed to compare the innate immunity transcriptome signature between COVID-19 and KD, and to analyze the interactions of these molecules with genes known to predispose to KD.MethodsTranscriptome datasets of COVID-19 and KD cohorts (E-MTAB-9357, GSE-63881, GSE-68004) were downloaded from ArrayExpress for innate immune response analyses. Network analysis was used to determine enriched pathways of interactions.ResultsUpregulations of IRAK4, IFI16, STING, STAT3, PYCARD, CASP1, IFNAR1 and CD14 genes were observed in blood cells of acute SARS-CoV-2 infections with moderate severity. In the same patient group, increased expressions of TLR2, TLR7, IRF3, and CD36 were also noted in blood drawn a few days after COVID-19 diagnosis. Elevated blood PYCARD level was associated with severe COVID-19 in adults. Similar gene expression signature except differences in TLR8, NLRP3, STING and IRF3 levels was detected in KD samples. Network analysis on innate immune genes and genes associated with KD susceptibility identified enriched pathways of interactions. Furthermore, higher expression levels of KD susceptibility genes HLA-DOB, PELI1 and FCGR2A correlated with COVID-19 of different severities.ConclusionOur findings suggest that most enriched innate immune response pathways were shared between transcriptomes of KD and COVID-19 with moderate severity. Genetic polymorphisms associated with innate immune dysregulation and KD susceptibility, together with variants in STING and STAT3, might predict COVID-19 severity and potentially susceptibility to COVID-19 related MIS-C.

FNDC1 Polymorphism (rs3003174 C > T) Increased the Incidence of Coronary Artery Aneurysm in Patients with Kawasaki Disease in a Southern Chinese Population.

BackgroundA large number of studies demonstrated that the key to the occurrence and development of Kawasaki disease (KD) is the over-activation of immune cells and the generation of various inflammatory factors, leading to the imbalance of the immune system. Recently, mutations in the FNDC1 gene have been shown to be associated with inflammatory responses. However, there have been no reports on the relationship between FNDC1 gene and KD so far.MethodsWe enrolled 1611 controls and 1459 patients with KD, including 372 patients with coronary artery aneurysm (CAA) and 179 patients with coronary artery lesion (CAL). The relationship between FNDC1 rs3003174 polymorphism and KD with CAA or without CAA was investigated.ResultsThis study showed no evidence that the association between FNDC1 rs3003174 C>T polymorphism and KD susceptibility was statistically significant (CT versus CC: adjusted odds ratio (OR) =0.897, 95% confidence interval (CI) =0.769–1.045, P=0.162; TT versus CC: adjusted OR=0.995, 95% CI=0.786–1.260, P=0.968; dominant model: adjusted OR=0.916, 95% CI=0.792–1.059, P=0.235; and recessive model: adjusted OR=1.055, 95% CI=0.845–1.316, P=0.638). However, our further stratified analysis in the control and KD group bore out that the incidence of TT genotype of FNDC1 rs3003174 C > T polymorphism was higher than that of CC/CT genotype in KD patients stratified by CAA (adjusted OR=1.437, 95% CI=1.034–1.996, P=0.031). Moreover, a stratified analysis of age and gender in KD patients indicated that the rs3003174 TT genotype increased the risk of CAA formation in aged ≦60 months (CC/CT vs TT: adjusted OR=1.580, 95% CI=1.106–2.259, P=0.012) and male (CC/CT vs TT: adjusted OR=1.653, 95% CI=1.101–2.481, P=0.015) KD patients.ConclusionThe results of this study demonstrated that the FNDC1 rs3003174 C>T polymorphism may be a hazard factor in the formation of CAA in KD patients that was not disclosed before.

Validation of genome-wide associated variants for Kawasaki disease in a Taiwanese case\u2013control sample

Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology that affects infants and young children. Considerable evidence supports the hypothesis that there is a genetic basis for KD susceptibility. Genome-wide association studies (GWAS) have identified several genetic variants associated with KD. This study aims to replicate three novel KD-associated single nucleotide polymorphisms (SNPs), identified by GWAS in Japanese, in a Taiwanese population. Associations between these SNPs and development of coronary artery lesions (CALs) were also investigated. The rs2254546 A/G, rs2857151 A/G, and rs4813003 C/T SNPs were genotyped in 681 children with KD and 563 ethnically-matched healthy controls using TaqMan Assay or DNA sequencing. We found rs2254546 and rs4813003 SNPs were significantly associated with KD (G allele, odds ratio [OR] = 1.54, P = 1.0 × 10–5; C allele, OR = 1.32, P = 8.1 × 10–4). However, no evidence for associations with CAL development was observed. Our study successfully validates associations of the rs2254546 and rs4813003 SNPs with KD in a Taiwanese population. Further functional studies of the SNPs are important in understanding the pathogenesis of KD.

The elevated serum levels of calcineurin and nuclear factor of activated T-cells 1 in children with Kawasaki disease

BackgroundThe calcineurin and nuclear factor of activated T-cells (CaN-NFAT) signaling pathway had been found to be associated with Kawasaki disease (KD) susceptibility and coronary artery aneurysm formation as a contributor. To evaluate serum calcineurin (CaN) and nuclear factor of activated T-cells 1(NFAT1) levels in patients with Kawasaki disease (KD).MethodsSerum levels of CaN and NFAT1 were measured by enzyme-linked immunosorbent assay method in 66 healthy children and 74 KD patients at acute, afebrile and subacute stage.ResultsThe serum levels of CaN and NFAT1 increased significantly in the acute stage, and decreased progressively in the afebrile and subacute stage, along with the reduction of C-reactive protein, white blood cells and neutrophil counts. And in the acute stage, the afebrile stage and the subacute stage, the expression of CaN and NFAT1 was upregulated significantly in KD patients compared to that in the healthy control. After the IVIG treatment, the serum levels of CaN and NFAT1 declined significantly in IVIG responders. However, the CaN and NTAT1 levels in the IVIG non-responders declined slowly. And in the afebrile stage, the NFAT1 levels were lower in KD patients with coronary artery lesions (CALs) (268.82 ± 11.96 ng/ml) than those without CALs (285.84 ± 25.13 ng/ml). However, the serum levels of CaN in KD patients with CALs had no significant difference with those in KD patients without CALs.ConclusionsThe specific regulation of CaN and NFAT1 serum levels in the course of KD was suggested that both of them were related in the development of KD.