kawasaki disease ( kd ) is an acute self - limiting form of vasculitis that afflicts infants and children and manifests itself as fever and signs of mucocutaneous inflammation . kd is characterized by prolonged fever , bilateral conjunctival infection , erythema of the oral mucosa , lips , and tongue , polymorphous rash , erythema of the palms and soles , and cervical lymphadenopathy.1 ) damage to the coronary arteries occurs in 15 - 25% of untreated individuals , and this has made kd the leading cause of pediatric acquired heart disease in developed countries.2 ) treatment with high - dose intravenous immunoglobulin ( ivig ) markedly reduces fever duration , systemic inflammation , and coronary artery lesion ( cal ) in children with kd , but about 10% of patients are unresponsive to ivig and demonstrate persistent or recurrent fever after initial ivig treatment.2 ) the average annual incidence of kd in korea is 134.4 per 100000 children < 5 years of age in 2011 , which is the second highest incidence of kd worldwide , following its incidence in japan.3 ) to date , the etiology of kd is still largely unknown . thus , no diagnostic test or prevention is available . in order to facilitate the genetic studies of kd , the korean kawasaki disease genetics consortium ( kkdgc ) was formed in 2008 with 10 hospitals . in this review paper , the overall research interests of the kkdgc are introduced , as well as its standardized forms and procedures . in order to collect a large number of the kd patients ' clinical data and genomic deoxyribonucleic acid ( dna ) samples for genetic studies of kd in korea , the first kkdgc was formed in 2008 with 10 hospitals and 1 company ( seoul clinical laboratories , scl ) . the consortium initially had set a goal to collect a total of 500 kd samples and achieved this goal in less than 2 years ( may 2008 to february 2010 ) by collecting a total of 517 kd samples . the collected clinical data and genomic dna samples were used for clinical data analysis and genetic studies of kd . however , it was realized that 500 kd case samples were not sufficient for large - scale genetic studies of kd . thus , the second consortium was started in 2012 ( april 2012 to september 2014 ) . through the first and second consortia , a total of 1198 kd case samples ( genomic dna and plasma samples ) and clinical data 1 ) . the collection of clinical data and genomic dna samples is still ongoing by way of the second kkdgc . the kd patients were recruited from 13 tertiary academic hospitals in korea that are currently participating in the kkdgc . all the kd patients were diagnosed by pediatricians , in accordance with the diagnostic criteria of the american heart association.2 ) at each participating hospital , approximately 5 ml of blood from a kd patient was sampled in an acid citrate dextrose or ethylenediamine tetraacetic acid tube after explanation and approval with the informed consents form . the collected patients ' blood samples were used for genomic dna preparation or establishment of epstein - barr virus - transformed b cell lines at scl ( fig . each patient 's sample and clinical data were recorded by a new sample identification ( i d ) system that uses a two - digit disease symbol ( kd ) , two - digit hospital i d , and a 3 digit - serial number ( e.g. , kd - as-001 ) . pediatricians at each participating hospital collected all clinical data of the kd patients , including detailed clinical signs and treatment response . finally , all the patients ' clinical data and genomic dna samples were deposited at asan medical center at seoul . in order to characterize the clinical features of korean children with kd prior to genetic studies , we constructed a standard clinical data collection form of kd with a total of 41 variables . the clinical data collection sheet is composed of : 1 ) patient 's personal information , 2 ) clinical signs and symptoms , 3 ) echocardiogram findings , 4 ) treatment responses , 5 ) family history and recurrence , and 6 ) clinical lab data ( fig . the clinical data were used to categorize the patient subgroups into a kd type ( complete vs. incomplete kd ) , kd patients with or without cals ( normal vs. cal ) , or ivig responsiveness ( responder vs. non - responder ) . using the clinical data of 478 kd patients collected during the first consortium , there was an investigation of the clinical features and risk factors associated with cal development and ivig nonresponsiveness in korean children with kd . we found that incomplete kd type , ivig nonresponse , fever duration of 7 days or longer , and cc / ac genotypes of the rs7604693 single nucleotide polymorphism ( snp ) in the peli1 gene , were significantly associated with the development of cals , with odds ratios ( ors ) ranging from 2.06 to 3.04.4 ) this study also found that a serum albumin level of 3.6 g / dl or lower was significantly associated with nonresponsiveness to ivig ( or=2.76 ; p=0.006).4 ) to examine the mechanism of ivig - resistance in kd patients , we initially performed cell proliferation assays after in vitro immunoglobulin treatment in various cell lines , including kd patient - derived b cell lines ( either ivig responder or ivig non - responder patient ) . both the kd patient - derived b cell lines equally exhibited dose - dependent cell death by in vitro immunoglobulin treatment . however , no difference in cell death was observed in either b cell lines derived from the responder kd patient or non - responder kd patient ( fig . this result suggests that the b cell may not play a role for ivig responsiveness in kd patients . in addition , to understand the mechanisms of ivig resistance in kd patients , we examined the gene expression profiles of b cell lines derived from ivig responsive ( n=2 ) or ivig nonresponsive kd patients ( n=3 ) . we observed 34 upregulated ( > 2-fold ) and 14 downregulated ( < 2 fold ) genes after in vitro immunoglobulin treatment in b cells.5 ) specifically , there was significant upregulation of gene expression in immune - related genes and downregulation in genes involved in cell - cycle after in vitro immunoglobulin treatment in b cell lines . however , there was no difference in the pattern of gene expression between ivig responders and ivig non - responders . this result suggests that the resistance of ivig treatment in kd patients is not mediated by the change of quantitative gene expression in specific genes after ivig treatment . furthermore , in vitro immunoglobulin treatment in b cell lines did not increase the expression of the inhibitory fcgr2b gene . therefore , this data suggest that the therapeutic effect of ivig treatment in kd patients is not mediated by either inhibitory fc receptor ( fcgr2b ) on b cells or b cell - mediated immune responses . we performed a genome - wide association study ( gwas ) using affymetrix snp array 6.0 in 186 kd patients and 600 healthy controls ( fig . one snp on chromosome 1p31 ( rs527409 ) and a peli1 locus on chromosome 2p13.3 ( rs7604693 ) was associated with kd susceptibility and cal formation , respectively.6 ) a subgroup analysis was also performed to identify ivig response genes and cal susceptibility using case samples only . it was found that a snp ( rs17136627 ) in the kcnn2 gene was significantly associated with cal formation , particularly with large aneurysms ( diameter > 5 mm ) ( or=12.6 , p=1.9610).7 ) this result indicates that the kcnn2 gene can have an important role in the development of coronary artery aneurysms in kd . furthermore , we also found a significant association of a crp promoter snp ( rs12068753 ) with a high crp level in kd ( beta=3.97 , p=1.1110 ) via the genetic association analysis of inflammatory biomarkers in kd patients.8 ) in addition , we collaborated with international kd genetics groups , including international kd genetics consortium , taiwan kd genetics consortium , and japan kd genetics consortium . in particular , we contributed to the studies validating the fcgr2a association with kd , performed by the international kd genetics consortium,9 ) and replication of b lymphoid tyrosine kinase association with kd that was carried out by taiwan kd genetics consortium.10 ) in addition , the meta - analysis of asian kd gwas data is under way with the japanese and taiwanese groups . currently , we are re - analyzing the clinical data of all collected kd patients ( n=~1200 ) to evaluate the effect of age , gender , family history status , recurrence status , and kd types , on clinical features of kd . we also plan to study the interaction of clinical risk factors and genetic risk factors in kd . in order to identify new kd susceptibility and subphenotype loci , we are performing another gwas using an illumina human omni1 snp chip with approximately 300 kd cases , concerning 16 cases with family history , 46 cases with recurrence , 119 cases with ivig non - responsiveness , and 52 cases with cals ( diameter > 5 mm ) . multiple subsets of kd cases will be very useful to detect the loci associated with the subphenotypes of kd in gwas data analysis . in the near future , we also plan to adopt the exome sequencing approach for kd genetic studies . as demonstrated above , consortium - based genetic studies are an effective way to identify the clinical risk factors and genetic risk factors of kd that may be affected by multiple genes and environmental factors . furthermore , the kkdgc will facilitate and contribute to the understanding of pathophysiological mechanisms of kd and the development of novel diagnosis , as well as treatment and prevention strategies .
in order to perform large - scale genetic studies of kawasaki disease ( kd ) in korea , the korean kawasaki disease genetics consortium ( kkdgc ) was formed in 2008 with 10 hospitals . since the establishment of kkdgc 
 , there has been a collection of clinical data from a total of 1198 patients , and approximately 5 ml of blood samples per patient ( for genomic deoxyribonucleic acid and plasma isolation ) , using a standard clinical data collection form and a nation - wide networking system for blood sample pick - up . in the clinical risk factor analysis using the collected clinical data of 478 kd patients , it was found that incomplete kd type , intravenous immunoglobulin ( ivig ) non - responsiveness , and long febrile days are major risk factors for coronary artery lesions development , whereas low serum albumin concentration is an independent risk factor for ivig non - responsiveness . 
 in addition , we identified a kd susceptibility locus at 1p31 , a coronary artery aneurysm locus ( kcnn2 gene ) , and the causal variant in the c - reactive protein ( crp ) promoter region , as determining the increased crp levels in kd patients , by means of genome - wide association studies . 
 currently , this consortium is continually collecting more clinical data and genomic samples to identify the clinical and genetic risk factors via a single nucleotide polymorphism chip and exome sequencing , as well as collaborating with several international kd genetics teams . 
 the consortium - based approach for genetic studies of kd in korea will be a very effective way to understand the unknown etiology and causal mechanism of kd , which may be affected by multiple genes and environmental factors .