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Aim: To analyze the impact of CD32a polymorphism rs1801274 on the occurrence of Kawasaki disease (KD) through the meta-analysis. Methods: The correlation between CD32a polymorphism rs1801274 and the susceptibility to KD was appraised using summarized odds ratios (ORs) with their 95% confidence intervals (95% CIs). Besides, stratification analyses were further implemented on the basis of ethnicity and control source, respectively. Between-study heterogeneity was checked adopting chi-square-based Q test, with p  < .05 as significant level. And results from Q test determined which model would be employed for OR calculation, fixed- or random-effects. Sensitivity analysis was accomplished to test the stability of final results. Potential publication bias among included studies was investigated using Begg's funnel plot and Egger's test. If publication bias was significant, its influence on overall estimates would be measured adopting the trim-and-fill method. Results: CD32a polymorphism rs1801274 significantly increased KD risk in total analysis under the comparisons of AA vs. GG, AA + AG vs. GG, AA vs. GG + AG, A vs. G and AG vs. GG (OR = 2.69, 95% CI = 1.39-5.20; OR = 2.00, 95% CI = 1.23-3.26; OR = 1.90, 95% CI = 1.23-2.94; OR = 1.77, 95% CI = 1.34-2.34; OR = 1.53, 95% CI = 1.07-2.19). After stratification analysis by ethnicity, similar tendency was also observed in Caucasian and Asian subgroups under corresponding genetic models. And parallel results were replicated in population-based and other-source subgroups after stratified analysis by control source, under some contrasts. Conclusion: CD32a polymorphism rs1801274 has strong relation to KD onset, and the presence of its A allele could elevate the disease incidence.

Kawasaki disease (KD) is an inflammatory disease in children associated with vasculitis affecting predominantly the coronary arteries and is now the most common cause of acquired heart disease in children in developed countries. The etiology of KD is unknown but epidemiological studies implicate an infectious agent or toxin, which causes disease in genetically predisposed individuals. The presence of immune complexes (ICs) in the serum of children with KD was established in numerous studies during the 1970s and 80s. More recent genetic studies have identified variation in Fcγ receptors and genes controlling immunoglobulin production associated with KD. In this review we link the genetic findings and IC studies and suggest a key role for their interaction in pathophysiology of the disease.

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C -ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C -ORF haplotype showed strong LD with, among others, rs201218628 ( FCGR2A -Q27W, r 2 = 0.63). LD between these two variants was weaker ( r 2 = 0.17) in Africans, whereas the FCGR2C -ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C -ORF haplotype and rs1801274 ( FCGR2A -H131R) were in weak LD ( r 2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C -ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.

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.

Previous research has found patients with the FcγRIIIB NA1 variant having increased risk of intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD). Our previous studies revealed that elevated FcγRIIA expression correlated with the susceptibility of KD patients. We conducted this research to determine whether and how Fcγ receptors affect the susceptibility, IVIG treatment response, and coronary artery lesions (CAL) of KD patients. The activating FcγRIIA and inhibitory FcγRIIB methylation levels of seven patients with KD and four control subjects were examined using HumanMethylation27 BeadChip. We enrolled a total of 44 KD patients and 10 control subjects with fevers. We performed real-time RT-PCR to determine the FcγRIIA and FcγRIIB expression levels, as well as a luciferase assay of FcγRIIA. We found a considerable increase in methylation of both FcγRIIA and FcγRIIB in KD patients undergoing IVIG treatment. Promoter methylation of FcγRIIA inhibited reporter activity in K562 cells using luciferase assay. The FcγRIIB mRNA expression levels were not found to increase susceptibility, CAL formation, or IVIG resistance. FcγRIIA mRNA expression levels were significantly higher in IVIG-resistant patients than in those that responded to IVIG during the pre-treatment period. Furthermore, the FcγRIIA/IIB mRNA expression ratio was considerably higher in KD patients with CAL than in those without CAL. FcγRIIA and FcγRIIB both demonstrated increased methylation levels in KD patients that underwent IVIG treatment. FcγRIIA expression influenced the IVIG treatment response of KD patients. The FcγRIIA/IIB mRNA expression ratio was greater in KD patients with CAL formation.

Objectives: The aim of this meta-analysis was to estimate the association between the FCGR2A rs1801274 polymorphism and the susceptibility to autoimmune diseases more precisely., Methods: A meta-analysis was conducted on the association between the FCGR2A gene variants and ADs by allelic contrast, homozygote contrast, the recessive model, and the dominant model., Results: A total of 17 studies with 30 comparisons in different populations and genotype-methods were available for this meta-analysis, including 10 Kawasaki disease (KD), 7 Ulcerative colitis (UC), 6 Crohn's disease (CD), 3 Rheumatoid arthritis (RA), 2 Systemic lupus erythematosus (SLE), 1 Autoimmune thyroid disease (ATD) and 1 diabetes mellitus type 1 (T1D). A significant association between FCGR2A rs1801274 polymorphism were found in KD (OR = 1.409, P < 0.001) and UC (OR = 1.237, P < 0.001). A overall meta-analysis increased risk of AD significant association between FCGR2A rs1801274 gene polymorphism and ADs under allelic (OR = 1.378, P=0.000), homozygous (OR: 1.866, P=0.001), dominant (OR = 1.667, P = 0.000) and recessive (OR = 1.434, P=0.000) in Asian population. Meanwhile, a decreased risk of AD was detected in the allelic (OR= 0.882, P = 0.011), homozygous (OR = 0.777, P = 0.013), dominant (OR = 0.850, P = 0.032) and recessive (OR = 0.840, P = 0.048) in African-American population., Conclusions: This meta-analysis demonstrates that the FCGR2A rs1801274 G-allele confers susceptibility to KD and UC. Data also suggests that the FCGR2A rs1801274 polymorphism may be associated with the susceptibility of multiple ADs in Asian and African-American populations., Competing Interests: The authors declare there are no conflicts of interests.

Background: Intravenous immunoglobulin (IVIG) is an efficacious treatment modality for a number of conditions and is usually well tolerated with few reports of serious adverse events; however, the administration of IVIG may occasionally result in clinically significant hemolysis., Study Design and Methods: The literature was reviewed for case reports and case series of IVIG-associated hemolysis. The cases were scrutinized for clues as to the possible mechanism(s) of the hemolysis., Results: Review of the 129 individual cases reported in the literature identifies clinical features shared by the majority of patients. These features included non-O blood group patients and treatment with high-dose IVIG as an immune-modulating agent for an underlying inflammatory or immune-mediated disorder. Other patient factors such as secretor phenotype, soluble ABH substance, and Fcgamma receptor polymorphisms may also play a role., Conclusions: It is known that high-dose IVIG given to non-O blood group patients with underlying inflammatory and/or immune-mediated disorders is associated with increased risk of hemolysis. This review reveals additional patient characteristics in cases of IVIG-associated hemolysis, including underrepresentation of D- and group B cases, higher incidence in pediatric Kawasaki disease and unique at-risk patient groups including allogeneic stem cell transplant recipients with group A donor in a group O recipient, and patients in whom soluble AB substance is removed by plasma exchange at the same time as receiving IVIG., (© 2015 AABB.)

Several previous studies have investigated whether the FCGR2A gene H131R polymorphism confers an increased risk of Kawasaki disease (KD), but conflicting results have been reported. To further explore the association of this polymorphism with KD susceptibility, we performed an extensive search of relevant studies and conducted a meta-analysis to obtain a more precise estimate of risk. Systematic searches of the electronic databases Embase, PubMed, and Google Scholar were performed to identify relevant studies. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used for statistical analysis. Six studies were included in the meta-analysis, involving 1709 patients with KD and 3207 controls. Significant association was found between the FCGR2A gene H131R polymorphism and KD risk in analysis of the total population (HH vs RR: OR = 1.97, 95%CI = 1.55-2.50; HH vs HR: OR = 1.38, 95%CI = 1.21-1.57; the dominant model: OR = 0.69, 95%CI = 0.60-0.78; and the recessive model: OR = 1.65, 95%CI = 1.32-2.07). In subgroup analysis by ethnicity, significant association was found between the H131R polymorphism and KD risk in Asians, but not in Caucasians. In addition, we found no significant association between the FCGR2A gene H131R polymorphism and risk of KD-associated coronary artery lesions. In conclusion, this meta-analysis suggested that the H131R polymorphism in the FCGR2A gene might be associated with susceptibility to KD in Asians.

Kawasaki disease is an acute, febrile syndrome in infancy, characterised by vasculitis of medium-sized arteries, and affects predominantly young children. Family-based studies on Kawasaki disease supports the contribution of genetic factors in disorder manifestation. In a recent genome-wide association study, the polymorphism rs1801274 of FCGR2A [Fc fragment of immunoglobulin G, low-affinity IIa, receptor] gene has been implicated in disease pathogenesis. The aim of the present study was to explore the association of this variant, for the first time, in a group of Kawasaki-diseased patients of Greek origin. A total of 47 Kawasaki-diseased children and 50 control subjects were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphism assay was performed in rs1801274 genotyping. No association was observed between this polymorphism genotypes' or alleles' distribution between Kawasaki-diseased patients and controls. Furthermore, no association was revealed between this polymorphism and cardiovascular complications in Kawasaki-diseased patients. In the literature, the reported data over this polymorphism association with Kawasaki disease in Caucasian patients are contradictory. In addition, the disease shows low prevalence in the Caucasian populations. Therefore, the independent genetic association studies on rs1801274 with Kawasaki disease in various Caucasian groups increase the amount of genetic data, which could be used in a future meta-analysis, increasing the statistical power of the resultant conclusions.

Objective: Kawasaki disease (KD) is characterized by systemic vasculitis, and it is the most common acquired heart disease in children. However, the etiology and immunopathogenesis of KD are still unclear. A genome-wide association study (GWAS) identified polymorphisms in CD40, BLK, and FCGR2A as the susceptibility genes for KD. No epigenetic array studies of KD have previously been published. This study was undertaken to investigate differences in DNA methylation in patients with KD as compared to controls., Methods: The HumanMethylation27 BeadChip (Illumina) was used to survey the differences in DNA methylation between KD patients and controls. DNA methylation array validation was performed in a separate cohort by pyrosequencing assay and reporter gene assays. Messenger RNA (mRNA) expression was determined, and the association of methylation with response to intravenous immunoglobulin (IVIG) treatment was analyzed., Results: HumanMethylation27 BeadChip assay showed a 15% difference in methylation of 10 genes between KD patients and controls. The FCGR2A cg24422489 group, which was recently reported to be associated with KD susceptibility in a GWAS, had significant hypomethylation of 15.54% less in the KD group than in the control group. Validation of FCGR2A methylation in another cohort also showed significant hypomethylation in the KD group (5 of 5 CpG sites [P < 0.01]; n = 43 in the KD group and n = 55 in the control group). KD patients with IVIG resistance showed hypomethylation of 5 CpG sites (P < 0.05). FCGR2A mRNA expression was significantly increased in patients in the acute stage of KD compared to controls. Reporter gene assays indicated that the CpG sites of the FCGR2A promoter region were sufficient to modulate gene expression., Conclusion: This is the first study to examine the DNA methylation array in KD and identify a role of hypomethylation of FCGR2A in susceptibility to KD and IVIG resistance., (Copyright © 2015 by the American College of Rheumatology.)

Some patients with autoimmune and inflammatory diseases treated with intravenous immunoglobulin G (IVIg) as a first line therapy are refractory. Identification of predictive biomarker(s) to segregate responders and non-responders to IVIg therapy remains critical. A number of biomarkers, particularly in Kawasaki disease, have shown potential for predicting response to IVIg., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Kawasaki disease (KD) is characterized by pediatric systemic vasculitis of an unknown cause. The low affinity immunoglobulin gamma Fc region receptor II-a (FCGR2A) gene was reported to be involved in the susceptibility of KD. DNA methylation is one of the epigenetic mechanisms that control gene expression; thus, we hypothesized that methylation status of CpG islands in FCGR2A promoter associates with the susceptibility and therapeutic outcomes of Kawasaki disease. In this study, 36 KD patients and 24 healthy subjects from out-patient clinic were recruited. Eleven potential methylation sites within the targeted promoter region of FCGR2A were selected for investigation. We marked the eleven methylation sites from A to K. Our results indicated that methylation at the CpG sites G, H, and J associated with the risk of KD. CpG sites B, C, E, F, H, J, and K were found to associate with the outcomes of IVIG treatment. In addition, CpG sites G, J, and K were predicted as transcription factors binding sites for NF-kB, Myc-Max, and SP2, respectively. Our study reported a significant association among the promoter methylation of FCGR2A, susceptibility of KD, and the therapeutic outcomes of IVIG treatment. The methylation levels of CpG sites of FCGR2A gene promoter should be an important marker for optimizing IVIG therapy.

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.

Objective: Kawasaki disease (KD), response to intravenous immunoglobulin (IVIG) therapy, and associated coronary artery disease progression have been associated with genetic polymorphisms in Fc gamma receptor (FcγR) genes. However, it is not known whether the existing gene copy number (GCN) variability relates to KD treatment response, susceptibility, or associated sequelae., Methods: The copy number of individuals with KD (n=510) and their family members (n=808) for three variable FcγRs was assessed using pyrosequencing. We performed the transmission disequilibrium test to examine the association of GCN for FcγRs (FcγR2C, FcγR3A, and FcγR3B) with susceptibility and used logistic regression models to determine its association with IVIG treatment outcomes., Results: FcγR2C and FcγR3B GCN were significantly associated with KD susceptibility. IVIG response was associated with GCN variations of FcγR3B in Whites and FcγR2C in Hispanics, and gene risk score based on single nucleotide polymorphism and GCN in FcγRs were significantly different between IVIG responders and nonresponders among Whites. We found no significant associations between coronary artery disease and any of the FcγR copy numbers., Conclusion: GCN of FcγR2C and FcγR3B influences IVIG treatment response and predisposes individuals to KD, providing potential insights into understanding the mechanism of the FcγR gene family in the IVIG pathway.

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 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 diffuse vasculitis occurring in children and showing predilection for the coronary arteries. The etiology remains unknown, although some risk factors for susceptibility have been defined. Asian ethnicity is a primary risk factor. Several theories have circulated regarding the differences in KD ethnic incidence. Those theories implicating genetic differences among populations as the cause for this discrepancy have dominated and are areas of active investigation by multiple research groups. Differences in diet between Asians and Westerners are touted as reasons for certain ethnic-related discrepancies in susceptibility to cardiovascular disease and cancer in adults. Surprisingly, these cultural dietary differences have not been previously considered as the source of the discrepancy in KD incidence among these ethnic populations. Recent data from genetic studies have highlighted the role of specific immune receptors in the pathogenesis of KD. Functions of the Fcγ receptors (FcGRs) are modulated by isoflavones in soy, in particular, genistein. Epidemiological data from Hawaiian populations support an association between soy consumption and KD. These observations form the basis of a hypothesis: isoflavones participate in KD pathogenesis by modulating function of the FcGRs and by disrupting the balance between activation and inhibition of the inflammatory response.

Background: A functional polymorphism in the inhibitory IgG-Fc receptor gene FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki disease (KD), a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (FcγRIIA, FcγRIIIA, and FcγRIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD., Methods and Results: We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA, and FcγRIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The FcγRIIA-131H variant showed an association with KD (P=0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16-1.96; P=0.002) for the primary combined population, which persisted in both white (P=0.04) and Asian (P=0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the FcγRIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders (P=0.0002) and specifically to white IVIG nonresponders (P=0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75-7.66; P=0.0006) and 3.60 (95% CI, 1.34-9.70; P=0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (OR(additive), 2.13; 95% CI, 1.11-4.0; P=0.02)., Conclusions: A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Kawasaki disease is an acute febrile syndrome in infancy, characterized by vasculitis of medium-sized arteries. Without treatment the disease can lead to coronary artery lesions (CAL) in approximately 25% of the children. Therapy consists of intravenous immunoglobulins (IVIG), leading to a decrease of complications to 5-16%. Little is known about the working mechanisms of IVIG. In this study we evaluated the involvement of Fcgamma receptors (FcgammaRs) in Kawasaki disease by the determination of the frequency of known single nucleotide polymorphisms (SNPs) in the genes coding for the FcgammaRs and compared this with frequencies in a cohort of healthy controls. There was no difference in the distribution of the functionally relevant genotypes for FcgammaRIIa-131H/R, FcgammaRIIb-232I/T, FcgammaRIIIa-158 V/F and FcgammaRIIIb-NA1/NA2 between the patient group and the healthy controls. Furthermore, there were no polymorphisms linked to the disease severity as indicated by the absence or development of CAL during the disease. Altered transcription or expression of FcgammaR on specific cell types of the immune system may still play a role in susceptibility and treatment success, but at a level different from the functional SNPs in FcgammaR genes tested in this study.

We evaluated whether there is a possible relationship between the effectiveness of gamma-globulin treatment for patients with Kawasaki disease (KD) and the polymorphism of Fcgamma RIIa, IIIb, and IIIa. Genomic DNA was extracted from whole blood collected from 56 patients with KD who received gamma-globulin treatment. The genotypes for Fcgamma RIIIb-NA(1, 2), Fcgamma RIIa-H/R131, and FcgammaRIIIa-F/V158 were determined to investigate the association between these polymorphisms and the development of coronary lesions (CALs). Twenty-three percent of patients with the HH allele for the Fcgamma RIIa polymorphism progressed to CALs, compared with 60% with the HR and RR alleles. HR and RR alleles may be a predictor of the progression of CALs in KD before the initiation of gamma-globulin therapy.