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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 (KD) is an acute, self-limited vasculitis, mainly affecting children younger than 5 years old, with accompanying fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) is the standard treatment for KD; however, ~15% of patients are resistant to IVIG treatment. To identify protein coding genetic variants influencing IVIG resistance, we re-analyzed our previous genome-wide association study (GWAS) data from 296 patients with KD, including 101 IVIG non-responders and 195 IVIG responders. Five nonsynonymous SNPs (nsSNPs) in five immune-related genes, including a previously reported SAMD9L nsSNP (rs10488532; p.Val266Ile), were associated with IVIG non-response (odds ratio [OR] = 1.89-3.46, P = 0.0109-0.0035). In a replication study of the four newly-identified nsSNPs, only one in the interleukin 16 (IL16) gene (rs11556218, p.Asn1147Lys) showed a trend of association with IVIG non-response (OR = 1.54, P = 0.0078). The same IL16 nsSNP was more significantly associated with IVIG non-response in combined analysis of all data (OR = 1.64, P = 1.25 × 10 -4 ). Furthermore, risk allele combination of the IL16 CT and SAMD9L TT nsSNP genotypes exhibited a very strong effect size (OR = 9.19, P = 3.63 × 10 -4 ). These results implicate IL16 as involved in the mechanism of IVIG resistance in KD.

Background: Kawasaki disease (KD), which is characterized by vasculitis, is prone to occur in patients under 5 years of age, has an ambiguous etiology, and displays coronary artery lesions as the chief complication. Previous studies have linked miRNA-149 to cancers, and rs2292832 T>C is related to allergic diseases and inflammatory bowel disease, which both show immune system disorders and coronary artery disease. Therefore, we performed a study concentrating on the association between the miRNA-149 rs2292832 T>C polymorphism and KD susceptibility., Methods: The subjects enrolled were 532 children with KD and 623 controls. We used TaqMan real-time PCR to obtain the genotypes of the rs2292832 T>C polymorphism., Results: Ultimately, no significant association was found between the miRNA-149 rs2292832 T>C polymorphism and KD susceptibility, even in stratification analysis., Conclusion: Our results indicated that in southern Chinese patients, the miRNA-149 rs2292832 T>C polymorphism did not affect KD susceptibility, which needs to be further confirmed., (© 2019 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals, Inc.)

Children with Kawasaki disease (KD) resistant to intravenous immunoglobulin (IVIG) have a higher incidence of coronary artery lesions (CAL). Despite the association between Purinergic receptor P2Y12 (P2RY12) polymorphism, KD genetic susceptibility, and CAL complications being proved, few studies have assessed the relationship between P2RY12 polymorphisms and IVIG resistance in patients with KD. We recruited 148 KD patients with IVIG resistance and 611 with IVIG sensitivity and selected five P2RY12 polymorphisms: rs9859538, rs1491974, rs7637803, rs6809699, and rs2046934. A significant difference in the genotype distributions between patients was only observed for the rs6809699 A > C polymorphism (AC vs. AA: adjusted odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.27-0.84, P =0.011; AC/CC vs. AA: adjusted OR = 0.47, 95% CI = 0.27-0.83, P =0.0084). After adjusting for age and gender, the carriers of the rs6809699 C allele had OR of 0.44 to 0.49 for IVIG sensitivity (AC vs. AA: adjusted OR = 0.48, 95% confidence interval (CI) = 0.27-0.84, P =0.011; AC/CC vs. AA: adjusted OR = 0.47, 95% CI = 0.27-0.83, P =0.0084) compared to the carriers of a rs6809699 AA genotype, suggesting the protective effect of this SNP against IVIG resistance. Moreover, individuals with all five protective polymorphisms experienced a significantly decreased IVIG resistance compared to that of individuals with up to three protective polymorphisms (adjusted OR = 0.27, 95% CI = 0.13-0.57, P =0.0006). Our results suggest that the P2RY12 rs6809699 polymorphism could be used as a biomarker to predict IVIG resistance in KD patients., Competing Interests: The authors declare no competing interests., (Copyright © 2020 Zhouping Wang et al.)

Background: miRNAs play important roles in a variety of diseases. Thus, the association between miRNA-196a2 rs11614913 T>C polymorphism and Kawasaki disease susceptibility is still unknown., Methods: We included 532 children with Kawasaki disease and 623 healthy children from South China, and their DNA was extracted for genotyping by TaqMan methodology. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association., Results: No significant associations were observed between the miRNA-196a2 rs11614913 T>C polymorphisms and Kawasaki disease risk (TC vs TT: adjusted OR = 1.04, 95% CI = 0.79-1.37; CC vs TT: adjusted OR = 0.87, 95% CI = 0.63-1.21; dominant model: adjusted OR = 0.99, 95% CI = 0.76-1.27; and recessive model: adjusted OR = 0.85, 95% CI = 0.64-1.13). There was also no significant correlation found in stratified analyses., Conclusion: This study suggests that miRNA-196a2 rs11614913 T>C may not be associated with Kawasaki disease susceptibility in a southern Chinese population. Larger, multicenter studies are needed to confirm our conclusions., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children., (Copyright © 2019. Published by Elsevier Inc.)

Background: The etiology of Moyamoya disease (MMD) remains unknown to a large extent. Immune and inflammation dysfunction may play a role in the pathogenesis of this rare disease. Coexisting Kawasaki disease (KD) with MMD were reported and both diseases have a feature of vasculopathy, raising the hypothesis that there may be some common pathologic factors. We investigated single nucleotide polymorphisms (SNPs) previously identified in KD and performed a genetic analysis among Chinese pediatric patients with MMD. Results: We analyzed patients' DNA for the SNPs in B lymphoid tyrosine kinase, CD40, and coatomer protein complex beta-2 subunit, which had been associated with KD by literatures. Genotyping was performed by sequencing the genetic regions containing the SNPs with customized primers. A total of 5 genotype polymorphisms were examined among 48 pediatric MMD cases and 50 healthy controls. The mean age of MMD children was 6.72 ± 3.63 years old, while 7.31 ± 3.79 in controls. We found two SNPs of CD40 were associated with MMD. Polymorphisms rs4813003 major allele CC and rs1535045 minor allele TT were significantly higher in MMD cases. The other SNPs showed no statistical difference between MMD cases and controls. Conclusions: Our findings provide evidence that there may be a relationship between MMD and auto-immune dysfunction. We hypothesize that these genetic features may lead to the pathogenesis within the vascular wall. Further study regarding whether CD40 can function as the personalized target of MMD should be investigated in future.

Background: Kawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected., Methods: To explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes., Results: The single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio = 7.19, 95% confidence interval 2.43-21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P = 0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3'-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD., Conclusion: These findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.

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).)

Objectives: Kawasaki disease (KD) is an acute systemic vasculitis of unknown aetiology that affects infants and young children. Recent reports of elevated serum high mobility group box 1 (HMGB1) level during the acute phase of KD and its relationship to poor response to IVIG treatment suggest a possible association of HMGB1 polymorphisms with KD. We investigated the association between the polymorphisms of the HMGB1 gene, KD susceptibility, coronary artery lesions, and KD response to IVIG treatment., Methods: Whole genome sequencing of the HMGB1 gene was performed to identify causative variants. Two tagging single nucleotide polymorphisms of the HMGB1 gene were selected using linkage disequilibrium analysis. The tagging single nucleotide polymorphisms were genotyped using the TaqMan Allelic Discrimination assay in a total of 468 subjects (265 KD patients and 203 controls)., Results: The HMGB1 single nucleotide polymorphisms were not associated with KD susceptibility. However, in KD patients, there was a significant association of rs1412125 with coronary artery lesions formation in the recessive model (GG vs AA + GA: odds ratio = 4.98, 95% CI = 1.69-14.66, P = 0.005). In addition, rs1412125 was associated with IVIG resistance in the recessive (GG vs AA + GA: odds ratio = 4.11, 95% CI = 1.38-12.23, P = 0.017) and allelic models (G vs A: odds ratio = 1.80, 95% CI = 1.06-3.06, P = 0.027)., Conclusion: The rs1412125 in HMGB1 might be a risk factor for the development of coronary artery lesions and IVIG resistance in KD patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Kawasaki disease (KD) is an acute systemic vasculitis that predominantly affects children, and it can result in coronary artery lesions. Cyclooxygenase-2 (COX-2) is involved in the conversion of arachidonic acid to prostaglandin H2, an important precursor of several prostaglandins. The aim of this study was to examine the association between COX-2 gene polymorphisms and susceptibility to KD., Methods: A total of 276 subjects (136 KD and 140 controls) were recruited. The analysis of two single nucleotide polymorphisms rs689466 (-1195G/A) and rs20417 (-765G/C) was respectively detected with polymerase chain reaction sequence-based typing methods., Results: Polymorphisms of rs689466 were significantly different between the normal controls and KD patients (χ 2  = 6.070 and 5.435, both p < 0.05). The frequencies of AA genotype and A allele of rs689466 in Kawasaki disease group were higher than that of control group (χ 2  = 4.832, p = 0.028, OR = 1.832, 95%CI = 1.064-3.124; χ 2  = 5.435, p = 0.028, OR = 1.491, 95%CI = 1.065-2.088)., Conclusion: This study provides the first evidence supporting an association between COX-2 gene polymorphisms and susceptibility of KD. The AA genotype and A allele of rs689466 confer predisposing factors to 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.)

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.

Background: Kawasaki disease is the leading cause of acquired heart disease in children from developed countries. The Interleukin-6/ Interleukin-12 cytokine family has many members, including the paradoxical anti- and pro-inflammatory Interleukin-27. Recent studies have demonstrated that Interleukin-27 plays a role in immune diseases. Given this, we sought to evaluate the association between Interleukin-27 genetic polymorphisms and Kawasaki disease in Chinese children.Methods and resultsInterleukin-27 was genotyped in 100 Kawasaki disease children and 98 healthy children (controls), resulting in the direct sequencing of eight Single-nucleotide Polymorphisms: rs17855750, rs40837, rs26528, rs428253, rs4740, rs4905, rs153109, and rs181206). There were no significant differences in Interleukin-27 genotypes between Kawasaki disease and control groups. Of the eight Single-nucleotide Polymorphisms, there was a significant increase in the risk of Kawasaki disease with coronary arterial lesions in children with the rs17855750 (T>G), rs40837 (A>G), rs4740 (G>A), rs4905 (A>G), rs153109 (T>C), and rs26528 (A>G) Single-nucleotide Polymorphisms. This was particularly true for rs17855750 (T>G), which had a greater frequency in Kawasaki disease children with coronary arterial aneurysm., Conclusion: These findings may be used as risk factors when assessing a child's likelihood of developing Kawasaki disease, as well as for the development of future therapeutic treatments for Kawasaki disease.

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).)

Objective: To investigate the distribution of adiponectin +45T/G and +276G/T polymorphisms and its association with the development of Kawasaki disease and coronary artery lesion (CAL)., Methods: A total of 81 children with Kawasaki disease (among whom 11 had CAL) and 100 normal children who underwent physical examination (control group) were enrolled in a case-control study. Sequencing was performed to investigate the distribution of adiponectin +45T/G and +276G/T polymorphisms., Results: There were no significant differences between the Kawasaki disease and control groups in the frequencies of TT, TG, and GG genotypes and T/G alleles of +45T/G polymorphism in the adiponectin gene (P>0.05). In the Kawasaki disease group, there were also no significant differences in the genotype and allele frequencies of the +45T/G polymorphism between the children with CAL and those without (P>0.05). There were significant differences between the Kawasaki disease and control groups in the frequencies of GG, GT, and TT genotypes and G/T alleles of +276G/T polymorphism in the adiponectin gene (P<0.05). GG genotype was a risk factor for the development of Kawasaki disease (OR=2.313, P=0.006). In the Kawasaki disease group, there was no significant difference in the genotype distribution of the +276G/T polymorphism between the children with CAL and those without (P>0.05)., Conclusions: The adiponectin +276G/T polymorphism may be associated with the development of Kawasaki disease, but not associated with CAL. The adiponectin +45T/G polymorphism may not be associated with Kawasaki disease or CAL.

Kawasaki disease (KD) is an acute systemic vasculitis that predominantly affects children and can result in coronary artery lesions (CALs). Thrombomodulin (TM) is a critical cofactor in the protein C anticoagulant system. The TM C1418T (rs1042579) polymorphism is associated with a high risk of cardiac-cerebral vascular diseases. But the association of the TM C1418T polymorphism with susceptibility to KD, CAL formation, and intravenous immunoglobulin (IVIG) resistance is still unclear. In our study, we examined the TM C1418T polymorphism in 122 children with KD and 126 healthy children and revealed the correlation between the TM C1418T polymorphism and KD, CAL formation, and IVIG resistance.

Purpose: Kawasaki disease (KD) is a mucocutaneous lymph node syndrome. It is mainly seen in young children under the age of five. KD is a multifactorial disorder that includes genetic variants. The present study investigated the association between KD and single nucleotide polymorphisms (SNPs) in the candidate gene early B cell factor 2 (EBF2), which is associated with inflammation markers., Materials and Methods: An SNP analysis was performed by whole exon sequencing of the EBF2 gene. Our study comprised a total of 495 subjects (295 KD patients and 200 unrelated normal controls) from a Korean population. Tag SNPs were discovered using the Haploview program. Genotyping of the EBF2 gene was performed with the TaqMan® assay with real-time PCR methods., Results: Polymorphism of rs10866845 showed a significant difference in allele frequency between KD patients and controls (p=0.040). The EBF2 gene polymorphisms were significantly associated with KD on logistic regression analysis., Conclusion: EBF2 gene variants can contribute to KD in the Korean population., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018.)

Background: IL-10, as a proinflammatory and anti-inflammatory cytokine, has been thought to have an important role in the development of Kawasaki disease. Variation in the IL-10 gene might lead to altered protein production, which may result in Kawasaki disease. Several studies have been performed to investigate the IL-10 -592 A/C polymorphism and Kawasaki disease risk. Unfortunately, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of the association between the IL-10 -592 A/C polymorphism and Kawasaki disease risk., Method: The association between the IL-10 -592 A/C polymorphism and Kawasaki disease risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Six studies were enrolled in the present meta-analysis., Results: Overall, no significant association between IL-10 -592 A/C polymorphism and Kawasaki disease risk was found under allele contrast (A versus C: OR=0.95, 95% CI=0.77-1.18, p=0.668), homozygote comparison (AA versus CC: OR=0.86, 95% CI=0.56-1.31, p=0.475), heterozygote comparison (CA versus CC: OR=0.88, 95% CI=0.65-1.19, p=0.479), recessive genetic model (AA versus CA/CC: OR=0.96, 95% CI=0.73-1.28, p=0.801), or dominant genetic model (AA/CA versus CC: OR=0.85, 95% CI=0.64-1.13, p=0.275)., Conclusions: We conclude that IL-10 -592 A/C polymorphism was not associated with Kawasaki disease risk in the Chinese population. However, more primary large-scale and well-designed studies are still required to further evaluate the interaction of IL-10 -592 A/C polymorphism with Kawasaki disease risk.

Aim: Kawasaki disease (KD) is a systemic vasculitis of children associated with cardiovascular sequelae. Proinflammatory cytokines play a major role in KD pathogenesis. However, their role is both influenced and modified by regulatory T-cells. IL-1 gene cluster, IL-6 and TNF-α polymorphisms have shown significant associations with some vasculitides. Herein we investigated their role in KD., Methods: Fifty-five patients with KD who were randomly selected from referrals to the main pediatric hospital were enrolled in this case-control study. Single nucleotide polymorphisms (SNPs) of the following genes were assessed in patients and 140 healthy subjects as control group: IL-1α at -889 (rs1800587), IL-1β at -511 (rs16944), IL-1β at +3962 (rs1143634), IL-1R at Pst-I 1970 (rs2234650), IL-1RN/A at Mspa-I 11100 (rs315952), TNF-α at -308 (rs1800629), TNF-α at -238, IL-6 at -174 (rs1800795) and IL-6 at +565., Results: Twenty-one percent of the control group had A allele at TNF-α -238 while only 8% of KD patients had A allele at this position (P = 0.003, OR [95%CI] = 0.32 [0.14-0.71]). Consistently, TNF-α genotype GG at -238 had significant association with KD (OR [95% CI] = 4.31 [1.79-10.73]). Most controls carried the CG genotype at IL-6 -174 (n = 93 [66.9%]) while GG genotype was the most common genotype (n = 27 [49%]) among patients. Carriers of the GG haplotype at TNF-α (-308, -238) were significantly more prevalent among the KD group. No association was found between IL-1 gene cluster, allelic or haplotypic variants and KD., Conclusion: TNF-α GG genotype at -238 and GG haplotype at positions -308 and -238 were associated with KD in an Iranian population., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Aim: Kawasaki disease (KD) is a systemic vasculitis of medium-sized arteries. High levels of interleukin 4 (IL-4) and the dominance of Th2 cytokines seem to be a key feature in the acute phase of KD. In this study, the role of IL-4 and IL-4R gene polymorphisms were investigated in Iranian children with KD., Methods: Fifty-five patients with KD and 140 healthy subjects as a control group were enrolled in this study. Single nucleotide polymorphisms (SNPs) of IL-4 gene at positions -1098 (rs2243248), -590 (rs2243250) and -33 (rs2070874), as well as IL-4RA gene at position +1902 (rs180275) were assessed in patients and the control group., Results: The C allele and CC genotype of IL-4 gene at position -590 and at position -33 had positive associations and the CT genotype at -590 was negatively associated with KD (odds ratio (95% CI) = 0.04 [0.01-0.09]). The haplotype TCC was more frequent among the patients, while the haplotypes TTT and TTC had a negative association with KD., Conclusion: IL-4 polymorphisms might be associated with KD in an Iranian population., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Purpose: Kawasaki disease (KD) is an acute systemic vasculitis. Both the etiology of KD and the erythema of Bacille Calmette-Guérin (BCG) injection sites observed in the disease are poorly understood. We investigated the association between KD and single nucleotide polymorphisms (SNPs) in two candidate genes: inositol 1,4,5-triphosphate 3-kinase (ITPKC), a well-studied KD-associated gene, and solute carrier 11a1 (SLC11A1), which is associated with the hypersensitive reaction to the BCG strain in Koreans., Materials and Methods: Associations between KD and SNPs in two genes were evaluated. Potential associations between BCG injection site erythema and SNPs in two genes were also evaluated. Gene-gene interactions between ITPKC and SLC11A1 in KD and BCG injection site erythema were also analyzed., Results: Three tagging SNPs in ITPKC and five tagging SNPs in SLC11A1 were genotyped in 299 KD patients and 210 control children. SNP rs28493229 in ITPKC was associated with KD and coronary artery complications. SNP rs77624405 in SLC11A1 was associated with KD. Comparisons of KD patients with and without BCG injection site erythema revealed that SNP rs17235409 in SLC11A1 was associated with erythema; no erythema-associated SNPs in ITPKC were identified. Interactions between ITPKC rs28493229&#95;GG and SLC11A1 rs17235409&#95;GA and between ITPKC rs10420685&#95;GG and SLC11A1 rs17235409&#95;AA were strongly associated with BCG injection site erythema., Conclusion: This study identified several important polymorphisms in the ITPKC and SLC11A1 genes in Koreans. The genetic variants identified in this study affected KD and erythema of BCG injection sites independently and through gene-gene interactions. Also, the effects of the polymorphisms were age-dependent., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018)

Kawasaki disease (KD), a systemic vasculitis of infants and children, manifests as fever and mucocutaneous inflammation. Although its etiology is largely unknown, the epidemiological data suggest that genetic factors are important in KD susceptibility. To identify genetic variants influencing KD susceptibility, we performed a genome-wide association study (GWAS) and replication study using a total of 915 children with KD and 4553 controls in the Korean population. Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with KD susceptibility (P<1.0 × 10 -5 ), including the previously reported BLK locus (rs6993775, odds ratio (OR)=1.52, P=2.52 × 10 -11 ). The other two loci were newly identified: NMNAT2 on chromosome 1q25.3 (rs2078087, OR=1.33, P=1.15 × 10 -6 ) and the human leukocyte antigen (HLA) region on chromosome 6p21.3 (HLA-C, HLA-B, MICA and HCP5) (rs9380242, rs9378199, rs9266669 and rs6938467; OR=1.33-1.51, P=8.93 × 10 -6 to 5.24 × 10 -8 ). Additionally, SNP rs17280682 in NLRP14 was associated significantly with KD with a family history (18 cases vs 4553 controls, OR=6.76, P=5.46 × 10 -6 ). These results provide new insights into the pathogenesis and pathophysiology of KD.

Background: Kawasaki disease (KD) is an acute febrile systemic vasculitis that disturbs coronary arteries. Patients' risks of adverse cardiovascular events and subclinical atherosclerosis have been found to significantly increase with polymorphisms of the human cytochrome P450. This current study aims to research the possible relationship between cytochrome P450, family 2, subfamily E and polypeptide 1 (CYP2E1) polymorphisms with KD., Methods: We selected 6 tag single-nucleotide polymorphisms (SNPs) of the CYP2E1 gene for TaqMan allelic discrimination assay in 340 KD patients and performed analysis on the clinical phenotypes and coronary artery lesions (CALs). CAL associations of tag SNPs were adjusted for age and gender in the logistic regression., Results: The KD patients with a CC genotype of rs915906 demonstrated a greater proportion of CAL formation (P = 0.009). Furthermore, the GG genotype frequencies of rs2070676 showed a significantly greater risk for CAL formation in KD patients (P = 0.007). However, the SNPs of the CYP2E1 gene did not influence CAL formation in the participating KD patients either with or without high-dose acetylsalicylic acid. Using the expression quantitative trait locus analyses, we found that the SNPs associated with CAL formation in KD also affected CYP2E1 expression in certain cell types., Conclusion: This study is the first to find that the risk of CAL formation is related to CYP2E1 gene polymorphisms in KD patients.

Kawasaki disease (KD) is an acute systemic vasculitis that can potentially cause coronary artery aneurysms in some children. KD occurs approximately 1.5 times more frequently in males than in females. To identify sex-specific genetic variants that are involved in KD pathogenesis in children, we performed a sex-stratified genome-wide association study (GWAS), using the Illumina HumanOmni1-Quad BeadChip data (249 cases and 1,000 controls) and a replication study for the 34 sex-specific candidate SNPs in an independent sample set (671 cases and 3,553 controls). Male-specific associations were detected in three common variants: rs1801274 in FCGR2A [odds ratio (OR) = 1.40, P = 9.31 × 10-5], rs12516652 in SEMA6A (OR = 1.87, P = 3.12 × 10-4), and rs5771303 near IL17REL (OR = 1.57, P = 2.53 × 10-5). The male-specific association of FCGR2A, but not SEMA6A and IL17REL, was also replicated in a Japanese population (OR = 1.74, P = 1.04 × 10-4 in males vs. OR = 1.22, P = 0.191 in females). In a meta-analysis with 1,461 cases and 5,302 controls, a very strong association of KD with the nonsynonymous SNP rs1801274 (p.His167Arg, previously assigned as p.His131Arg) in FCGR2A was confirmed in males (OR = 1.48, P = 1.43 × 10-7), but not in the females (OR = 1.17, P = 0.055). The present study demonstrates that p.His167Arg, a KD-associated FCGR2A variant, acts as a susceptibility gene in males only. Overall, the gender differences associated with FCGR2A in KD provide a new insight into KD susceptibility.

Kawasaki disease (KD) is an acute systemic vasculitis complicated by development of coronary artery lesions. PECAM-1 is a kind of cell adhesion molecule, which plays an important role in coronary artery disease. The relationship between PECAM-1 gene polymorphisms and their susceptibility to Kawasaki diseases (KD) is still unclear. In our study, we examined the PECAM-1 gene polymorphisms in 44 KD patients and 59 healthy children and revealed the correlation of PECAM-1 gene polymorphisms in KD children with and without coronary artery lesions (CAL).

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.)

Unlabelled: Kawasaki disease (KD) is a systemic vasculitis childhood disease frequently complicating coronary artery lesions (CALs). Recently, the gene encoding a disintegrin and metalloprotease 17 (ADAM17) was found to modify vascular pathology in humans by differentially regulating the transforming growth factor-β (TGF-β) signaling pathway, which affects KD/CAL susceptibility. To explore the potential role of ADAM17 in KD occurrence and outcomes, we investigated the association of 28 single nucleotide polymorphisms (SNPs) in ADAM17 and three pathway genes of TGF-β signaling with KD phenotypes in a Han Chinese population, including 392 KD patients and 421 non-KD controls. Three ADAM17 SNPs showed an association with KD risk, which was further confirmed by haplotype analysis. The effect of ADAM17 on KD was also shown by multi-variable logistic regression analysis. In two-locus model analyses with SNPs in ADAM17 and TGF-β signaling pathway genes, stronger compound effects on the risk of KD and secondary CAL formation were observed relative to comparable single SNPs., Conclusion: Our results suggest that ADAM17 contributes to the KD risk and is involved in secondary CAL formation via the TGF-β/SMAD3 signaling pathway. This further enriches our understanding of the importance of the signaling pathway in KD occurrence and outcomes., What Is Known: • The transforming growth factor (TGF)-β/SMAD3 signaling pathway greatly influences susceptibility to Kawasaki disease (KD) and secondary coronary artery lesions (CALs) and/or the treatment response of intravenous immunoglobulin. • A disintegrin and metalloprotease 17 (ADAM17) effectively reduces TGF-β signaling by cleaving TGF-β receptor type-1, while ADAM17 genetic variants modify human vascular pathology by differentially regulating this signaling although it is unknown whether ADAM17 contributes to KD phenotypes. What is New: • ADAM17 genetic variants were shown to be associated with KD risk, even when excluding the influence of TGF-β signaling pathway genes, suggesting that ADAM17 is an important KD susceptibility-related genetic locus. • The more significant compound effects of two-locus models, combining single nucleotide polymorphisms (SNPs) in ADAM17 and other TGF-β signaling pathway genes including TGFB2 and SMAD3, on KD phenotypes relative to single SNPs suggest that ADAM17 is also involved in secondary CAL formation and confers the risk of KD/CALs via the TGF-β/SMAD3 signaling pathway.

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.

Kawasaki disease (KD) is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL) formation. We examined 384 single-nucleotide polymorphisms (SNPs) for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73), KD patients without CAL (n = 153), and cohort controls (n = 575). Individual SNPs were first assessed by univariate analysis (UVA) and multivariate analysis (MVA). We used multifactor dimensionality reduction (MDR) to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10), while 35 individual SNPs were significantly associated using MVA (p ≤ 0.05). Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ≤ 0.05). In logistic regression, combined possession of PDE2A (rs341058) and CYFIP2 (rs767007) significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10(-7)), while combinations of LOC100133214 (rs2517892) and IL2RA (rs3118470) significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10(-5)). Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

Objective: To investigate the association of single nucleotide polymorphisms (SNP) rs22833188 and rs2833195 in TIAM1 gene with the susceptibility to Kawasaki disease (KD) and its clinical characteristic in children., Methods: A case-control study was performed in this study. One hundred and eighty-eight children with KD and 197 normal children served as controls were enrolled. The genotypes of two SNPs rs22833188 and rs2833195 in TIAM1 gene were detected using PCR-RFLP., Results: There were no significant differences in the genotype (AA, AG and GG) and allele frequencies of SNP rs2833188 between the KD and control groups. Significant differences in the genotype (CC, GC and GG) frequency of SNP rs2833195 were noted between the KD and control groups (P=0.017). The frequency of C allele in the KD group was higher than in the control group (P=0.015). The polymorphism of SNP rs2833188 was associated with the occurrence of rash (P=0.011), and the polymorphism of SNP rs2833195 was associated with the occurrence of conjunctival hyperemia (P=0.021)., Conclusions: The polymorphism of rs2833195 in TIAM1 gene is associated with the susceptibility to KD. The polymorphisms rs2833188 and rs2833195 in TIAM1 gene may be associated with some clinical characteristics in children with KD.

Objective: To study the association of single nucleotide polymorphisms (SNPs, rs223895 and rs223899) in TARC/CCL17 gene with Kawasaki disease (KD) and its clinical characteristics in Han children from Central China., Methods: A case-control study was performed on 218 children with KD and 248 normal control children. The genotypes of SNPs (rs223895 and rs223899) in TARC/CCL17 gene were determined by polymerase chain reaction-restriction fragment length polymorphism. The association between the SNPs in TARC/CCL17 gene and the clinical characteristics of KD was assessed., Results: There were significant differences in the genotype (CC, CT, TT) and allele frequencies of SNP rs223895 between children with KD and controls (P<0.05), and C allele was a risk factor (OR=1.397). However, no significant differences were found between the two groups in the genotype and allele frequencies of SNP rs223899. Compared with those with other genotypes (CT+TT) of SNP rs223895, patients with CC genotype had significantly lower hemoglobin (Hb) and albumin (Alb) levels (P<0.05) and a significantly higher erythrocyte sedimentation rate (ESR) (P<0.05)., Conclusions: The SNP rs223895 in TARC/CCL17 gene is associated with the susceptibility to KD, and C allele is a risk factor. Moreover, SNP rs223895 may influence the levels of Hb, Alb, and ESR.

Kawasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries including the United States. The etiology of KD is not known; however, epidemiological and immunological data suggest infectious or immune-related factors in the manifestation of the disease. Further, KD has several hereditary features that strongly suggest a genetic component to disease pathogenesis. Human leucocyte antigen (HLA) loci have also been reported to be associated with KD, but results have been inconsistent, in part, because of small study samples and varying linkage disequilibrium (LD) patterns observed across different ethnic groups. To maximize the informativeness of single nucleotide polymorphism (SNP) genotypes in the major histocompatibility (MHC) region, we imputed classical HLA I (A, B, C) and HLA II (DRB1, DQA1, DQB1) alleles using SNP2HLA method from genotypes of 6700 SNPs within the extended MHC region contained in the ImmunoChip among 112 White patients with KD and their biological parents from North America and tested their association with KD susceptibility using the transmission disequilibrium test. Mendelian consistency in the trios suggested high accuracy and reliability of the imputed alleles (class I = 97.5%, class II = 96.6%). While several SNPs in the MHC region were individually associated with KD susceptibility, we report over-transmission of HLA-C*15 (z = +2.19, P = 0.03) and under-transmission of HLA-B*44 (z = -2.49, P = 0.01) alleles from parents to patients with KD. HLA-B*44 has been associated with KD in other smaller studies, and both HLA-C*15 and HLA-B*44 have biological mechanisms that could potentially be involved in KD pathogenesis. Overall, inferring HLA loci within the same ethnic group, using family-based information is a powerful approach. However, studies with larger sample sizes are warranted to evaluate the correlations of the strength and directions between the SNPs in MHC region and the imputed HLA alleles with KD., (© 2015 John Wiley & Sons Ltd.)

Objective: To study the association between two single nucleotide polymorphisms (rs4810485 and rs1535045 in CD40 gene) and Kawasaki disease (KD) in Han Chinese children., Methods: A case-control study was performed on 184 children with KD and 206 normal controls. The polymorphisms of two SNPs in CD40 gene were detected using PCR-RFLP., Results: There were no significant differences in the genotype distribution and allele frequency of SNP rs4810485 in CD40 gene between the KD and normal groups (P&gt;0.05). The genotype distribution of SNP rs1535045 in CD40 gene in the KD group was significantly different from the control group (P&lt;0.05). T allele of SNP rs1535045 was shown as a risk factor for development of KD (OR=1.592, 95%CI: 1.182-2.144, P=0.004). There were no association between the polymorphisms of the two SNPs and coronary artery lesions (P&gt;0.05)., Conclusions: SNP rs1535045 may be associated with the development of KD in Han Chinese children, while SNP rs4810485 may not.

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.

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.

Kawasaki disease (KD) is a multi-systemic vasculitis that preferentially affects children. A single nucleotide polymorphism (SNP) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) has been identified to be an important polymorphism in the risk of KD. This study was conducted to comprehensively investigate the associations between all tagging SNPs of ITPKC in the risk of KD in a Taiwanese population. A total of 950 subjects (381 KD patients and 569 controls) were recruited. Seven tagging SNPs (rs11673492, rs7257602, rs7251246, rs890934, rs10420685, rs2607420, rs2290692) were selected for TaqMan allelic discrimination assay. Clinical data of coronary artery lesions (CAL) and aneurysms were collected for analysis. A significant association was found between rs7251246 in ITPKC and CAL formation. Haplotype analysis for ITPKC polymorphisms also confirmed this association in the patients with CAL and aneurysm formation. This is the first study to identify that SNP rs7251246 in ITPKC is associated with the severity of KD.

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.

Objective: To examine the single nucleotide polymorphism (SNP) (rs1495592) in transforming growth factor-beta receptor 2 (TGFBR2) gene in children, and to investigate its association with Kawasaki disease (KD) and coronary artery lesions (CALs)., Methods: Thirty-five KD patients, 14 of whom had CALs (CAL subgroup), were selected as the case group, and 25 healthy age-matched children were selected as the control group. The SNP (rs1495592) in TGFBR2 gene was studied by gene sequencing. The association of SNP (rs1495592) with KD and (CALs) was analyzed based on the sequencing results., Results: There were no significant differences in genotype frequency distribution (χ(2)=0.566, P=0.452) and allele frequency distribution (χ(2)=0.216, P=0.642) between the two groups. Genotypes in the CAL subgroup included CC (21.4%) and CT+TT (78.6%), while genotypes in the non-CAL subgroup included CC (61.9%) and CT+TT (38.1%). There was significant difference in genotype frequency distribution between the two groups (χ(2)=5.546, P=0.019), but without significant difference in allele frequency distribution (χ(2)=3.673, P=0.055)., Conclusions: The SNP (rs1495592) in TGFBR2 gene may not be associated with development of KD in children, but it is associated with CALs in children with KD.

Objective: Kawasaki disease (KD) is a common autoimmune vasculitis. It has been regarded as the leading cause of acquired heart disease in children. This study aimed to assess the relationship between genome-wide association study (GWAS)-linked gene loci and KD., Method: By March of 2013, the published GWAS literatures of KD were retrieved from the databases including PubMed, MEDLINE, Web of Science, Cochrane Library, CNKI, VIP and Wanfang, and the gene loci associated with KD at genome-wide significance of P < 5.0×10(-8) were determined. For each of the gene loci, one single-nucleotide polymorphism (SNP) with strong association with KD was chosen for meta-analysis. Then the published case-control studies reporting the associations of the SNPs with KD were collected from English and Chinese databases with the same criteria. The Meta-analyses were conducted with RevMan 5.1 software after screening and evaluation., Result: A total of 4 gene loci including FCGR2A, BLK, CD40 and HLA were observed having association with KD at genome-wide significance of P < 5.0×10(-8) in at least one GWAS. The risk alleles of the SNPs in the gene loci were all more common in patients with KD relative to controls in the systematic reviews with 8, 4, 6 and 4 extracted case-control studies, respectively[ FCGR2A rs1801274: P < 0.001, OR = 1.40, 95% CI (1.30, 1.51); BLK rs2254546: P < 0.001, OR = 1.69, 95% CI (1.52, 1.88); CD40 rs4813003: P < 0.001, OR = 1.31, 95% CI (1.22, 1.41); HLA rs2857151: P < 0.001, OR = 1.41, 95% CI (1.27, 1.57)]. The significant publication bias was not observed in the meta-analyses., Conclusion: Our results confirmed the overall association of the 4 gene loci with KD in observed populations, together with the consistent presence of the relationship between BLK or HLA and KD in the populations, suggesting that it is hopeful to find the genetic marker combination predicting the risk of KD, the formation of secondary coronary artery lesions and the resistance of intravenous immunoglobulin, by further seeking the function SNPs of the gene loci and investigating the effect on the important clinical phenotypes of KD.

Objective: To investigate the association of rs72689236, a new functional single nucleotide polymorphism (SNP) of the gene encoding caspase-3 (CASP3), with the occurrence and development of Kawasaki disease by a meta analysis., Methods: A literature search was performed using databases at home and abroad according to inclusion and exclusion criteria, to acquire studies on the relationship between rs72689236 and Kawasaki disease published up to November 2012, including case-control studies and transmission disequilibrium tests. An integrated meta analysis was performed using RevMan 5.1 software after the studies were screened and evaluated., Results: Six studies were extracted for systematic review of the association between rs72689236 and Kawasaki disease. The frequency of allele A of the SNP was significantly higher in patients with Kawasaki disease than in the controls (OR=1.34, 95%CI=1.24-1.46, P<0.001); the risk for Kawasaki disease in children with allele A (AA+AG) increased by approximately 44% compared with children with GG (OR=1.44, 95%CI=1.27-1.65, P<0.001). The frequency of allele A of the SNP was significantly higher in Kawasaki disease patients with coronary artery lesions than in those without coronary artery lesions (OR=1.51, 95%CI=1.10-2.07, P= 0.01); the risk for coronary artery lesions in Kawasaki disease patients with allele A (AA+AG) increased by approximately 59% compared with Kawasaki disease patients with GG (OR=1.59, 95%CI= 1.00-2.53, P=0.05]. No association between this SNP and the therapeutic effect of intravenous immunoglobulin (IVIG) was found in patients with Kawasaki disease., Conclusions: The allele A of functional SNP rs72689236 of CASP3 increases the risk for Kawasaki disease, and it may be used as the genetic marker for susceptibility to coronary artery lesions as a complication of Kawasaki disease. Currently, there is still no sufficient evidence that this SNP has an impact on the therapeutic effect of IVIG in patients with Kawasaki disease, and more studies are needed to investigate the feasibility of its application in individualized treatment.

Objective: The minor allele T of rs113420705 (C/T) in caspase-3 gene (CASP3) has been found to significantly increase the risk of Kawasaki disease (KD) and complicate coronary artery lesions (CALs) in Japanese children. In this study, we have explored association of single nucleotide polymorphisms (SNPs) of CASP3 gene and clinic phenotypes of KD., Methods: A total of 238 unrelated KD patients and 364 healthy controls with matched age, gender and ethnic origins were recruited. Genotypes of the 3 SNPs were determined with PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Allelic, genotypic and haplotypic frequencies were compared between patients and controls, patients with and without CALs, and patients resistant to and responsive to intravenous immunoglobulin (IVIG) treatment., Results: The T allele and T carriers of rs113420705 were significantly more common in KD patients than controls. A significant difference was also detected in haplotype distribution between patients and controls, where two haplotypes involving the T allele of rs113420705 showed higher frequencies in the patient group. Allelic and genotypic frequencies of the 3 SNPs were similar between patients with and without CALs and those resistant to and responsive to IVIG treatment., Conclusion: Our results suggested that CASP3 probably plays an important role in KD. The T allele of rs113420705 may provide a useful marker for KD susceptibility, although no association between this SNP and clinical prognosis and treatment effect of KD has been found among the selected Chinese children patients.

Objective: To study the association of FCGR2A gene single nucleotide polymorphism (SNP) rs1801274 with Kawasaki disease (KD) susceptibility and the efficacy of intravenous immunoglobulin (IVIG) therapy in Han Chinese children., Methods: Thirty-five KD children and 25 age-and gender-matched healthy children (control group) were enrolled in the study. Polymerase chain reaction (PCR) and gene sequence analysis were applied to detect SNP of FCGR2A gene rs1801274. These KD patients were classified into two subgroups based on the presence of coronary artery lesion (CAL) following IVIG therapy: CAL (n=13) and non-CAL (n=22)., Results: FCGR2A gene SNP rs1801274 was detected in all subjects, including three genotypes (AA, AG and GG). For FCGR2A gene SNP rs1801274, there were significant differences in the genotype and allele frequencies between the KD and control groups (P<0.05), and significant differences in the genotype and allele frequencies were also found between the CAL and non-CAL subgroups (P<0.05). A allele and AA genotype were linked to an increased risk of KD susceptibility (A allele: OR=3.39, 95%CI:1.53-7.50; AA genotype: (OR=4.93, 95%CI:1.61-15.1). Both AG (OR=5.43, 95%CI:1.06-27.8) and G allele (OR=4.88, 95%CI:1.44-16.5) were linked to an increased risk of CAL in KD children., Conclusions: Polymorphism of the FCGR2A gene SNP rs1801274 is one of the important factors probably influencing susceptibility to KD and efficacy of IVIG therapy on KD in Han Chinese children.

Kawasaki disease (KD) is a multi-systemic vasculitis which preferentially affects infants and children. A single nucleotide polymorphism (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) was identified to be associated with the increased risk of KD; however, in more recent studies associations have been controversial. Thus, we performed a meta-analysis, integrating case-control and transmission/disequilibrium test (TDT) studies, to investigate the relationship between this polymorphism and risk of KD. A total of ten case-control and two TDT studies, comprising 3,821 cases, 12,802 controls and 949 families, were included in this meta-analysis. There was a significant association between the C allele of rs28493229 and the increased risk of KD (OR = 1.53, 95 % CI = 1.34-1.74, P < 0.001), by the random-effects model because of heterogeneity (Q = 27.67, P (heterogeneity) = 0.004). Nevertheless, it was screened out by meta-regression analysis that the coronary artery lesions (CALs) status of KD could partly explain the heterogeneity, with consistently significant associations in both subgroups after stratification by CALs status. Moreover, estimates before and after the deletion of each study were similar in sensitivity analysis, indicating robust stability of the meta-analysis. This meta-analysis reveals that the functional polymorphism rs28493229 in ITPKC significantly contributes to the risk of KD.

Kawasaki disease (KD) is characterized by acute systemic vasculitis and frequently is complicated by coronary artery lesions (CALs). The inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene rs28493229 was recently found to be associated with the risk for KD in the Japanese population, suggesting that the ITPKC gene may contribute to KD susceptibility. This study investigated the association of ITPKC polymorphisms with KD in a Han Chinese population. Five ITPKC Single-nucleotide polymorphisms, including rs28493229, were genotyped in 223 unrelated patients who had KD and 318 non-KD control subjects. The allele, genotype, and haplotype frequencies were compared between the patients and the control subjects, between the patients with and those without CALs, and between patients resistant to intravenous immunoglobulin treatment and those responsive to such treatment. Multiple alleles were observed for rs28493229 and rs2290692. No significant differences in the frequencies of the C allele, the CC genotype, or the C carriers of rs28493229 were observed in the comparisons. Interestingly, significantly higher frequencies of the C allele (p < 0.001), the CC genotype (p = 0.001), and the C carriers (p = 0.003) were observed for rs2290692 among the patients than among the control subjects, and similar differences were observed between the patients with and those without CALs. The GC haplotype for rs28493229 and rs2290692 was more common among the patients than among the control subjects. The results indicate that the C allele of the ITPKC gene rs2290692 is linked to a significantly higher risk for KD in the studied population, which provides new evidence to support the importance of the ITPKC gene in the occurrence of KD. More notably, this finding suggests that there may be an unidentified ITPKC polymorphism in strong linkage disequilibrium to rs2290692, significantly affecting susceptibility to KD in the Han population.

Background: Coronary artery lesions (CAL) are a serious complication of Kawasaki disease (KD). The increased serum E-selectin level during the acute phase of KD and the association of E-selectin gene (SELE) polymorphisms with the prevalence of coronary artery disease in adults suggest a possible association between SELE polymorphisms and the development of CAL in KD patients., Methods: The subjects consisted of 177 KD patients, including 59 with and 118 without CAL, and 305 healthy controls. Two single nucleotide polymorphisms (SNP) of SELE, 98G>T (rs1805193) and Ser128Arg (rs5361), were genotyped by direct sequencing and the high-resolution melting curve method, respectively. The allele distributions were assessed using the chi-squared test., Results: There were no significant differences in the T allele frequency at 98G>T between KD patients and controls (1.4% vs 1.0%, P = 0.55) or between KD patients with and without CAL (1.7% vs 1.3%, P = 0.77). Similarly, there were no differences in the distribution of the C allele (128Arg) at Ser128Arg between KD patients and controls (4.5% vs 3.4%, P = 0.40) or between KD patients with and without CAL (4.2% vs 4.7%, P = 0.86)., Conclusion: Although no association was detected between these SELE polymorphisms and the prevalence of KD or the development of CAL, this may have been due to the study limitations, including a low frequency of the minor alleles and a small sample size. A larger-scale association study is needed in order for a definitive conclusion to be made as to whether these SNP are associated with susceptibility to KD or not., (© 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.)

To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10(-8)). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis.

We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.

Background: Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. Our previous studies showed expression of CD40 ligand on CD4+ T cells correlated to the coronary artery lesion (CAL) and disease progress in KD. Other studies from Japan suggested the role of CD40L in the pathogenesis of CAL, and this might help explain the excessive number of males affected with KD but cannot be reproduced by Taiwanese population. This study was conducted to investigate the CD40 polymorphism in KD and CAL formation., Methods: A total of 950 subjects (381 KD patients and 569 controls) were investigated to identify 2 tagging single-nucleotide polymorphisms (tSNPs) of CD40 (rs4810485 and rs1535045) by using the TaqMan allelic discrimination assay., Results: A significant association was noted with regards to CD40 tSNPs (rs1535045) between controls and KD patients (P = 0.0405, dominant model). In KD patients, polymorphisms of CD40 (rs4810485) showed significant association with CAL formation (P = 0.0436, recessive model). Haplotype analysis did not yield more significant results between polymorphisms of CD40 and susceptibility/disease activity of KD., Conclusions: This study showed for the first time that polymorphisms of CD40 are associated with susceptibility to KD and CAL formation, in the Taiwanese population.