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.
The average annual incidence of KD in South Korea has continuously increased to 134.4 per 100,000 children <5 years of age in 2011, which is the second highest incidence of KD worldwide, following its incidence in Japan.
Background: Community-acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality. Its disease burden varies by age and etiology and is time dependent. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. Methods: We conducted a retrospective study in 30,994 children (aged 0-18 years) with CAP between 2010 and 2015 at 23 nationwide hospitals in South Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified as macrolide-sensitive MP, macrolide-less effective MP (MLEP), and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. Results: MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.4% of the total MP pneumonia. In children < 2 years of age, RSV (34.0%) was the most common cause of CAP, followed by MP (9.4%); however, MP was the most common cause of CAP in children aged 2-18 years of age (45.3%). Systemic corticosteroid was most commonly administered for MP pneumonia. The rate of hospitalization in intensive care units was the highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia.
Kawasaki disease (KD) is an acute self-limited vasculitis of infants and children that manifests as fever and signs of mucocutaneous inflammation. Coronary artery aneurysms develop in approximately 15-25% of untreated children. Although the etiology of KD is largely unknown, epidemiologic data suggest the importance of genetic factors in the susceptibility to KD. In order to identify genetic variants that influence KD susceptibility, we performed a genome-wide association study (GWAS) using Affymetrix SNP array 6.0 in 186 Korean KD patients and 600 healthy controls; 18 and 26 genomic regions with one or more sequence variants were associated with KD and KD with coronary artery lesions (CALs), respectively (p < 1 × 10(-5)). Of these, one locus on chromosome 1p31 (rs527409) was replicated in 266 children with KD and 600 normal controls (odds ratio [OR] = 2.90, 95% confidence interval [CI] = 1.85-4.54, P (combined) = 1.46 × 10(-6)); and a PELI1 locus on chromosome 2p13.3 (rs7604693) was replicated in 86 KD patients with CALs and 600 controls (OR = 2.70, 95% CI = 1.77-4.12, P (combined) = 2.00 × 10(-6)). These results implicate a locus in the 1p31 region and the PELI1 gene locus in the 2p13.3 region as susceptibility loci for KD and CALs, respectively.
Aim: To investigate the influence of peroxisome proliferator-activated receptor γ2 (PPAR-γ2) gene polymorphism rs1801282 and protein tyrosine phosphatase receptor type D (PTPRD) gene polymorphism rs17584499 on the occurrence of type 2 diabetes and pioglitazone efficacy in a Chinese Han population. Methods: One hundred ninety seven type 2 diabetes patients and 212 healthy controls were enrolled. Among them, 67 type 2 diabetes patients were administered pioglitazone (30 mg/d, po) for 3 months. All the subjects were genotyped for genetic variants in PPAR-γ2 and PTPRD using MALDI-TOF mass spectrometry. Fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, serum triglyceride, total cholesterol, low-density and high-density lipoprotein-cholesterol were determined. Results: The PPAR-γ2 gene rs1801282 polymorphism was significantly associated with type 2 diabetes susceptibility (OR=0.515, 95% CI 0.268-0.990) and the PTPRD gene rs17584499 polymorphism was also significantly associated with type 2 diabetes (OR=1.984, 95% CI 1.135-3.469) in a dominant model adjusted for age, gender and BMI. After pioglitazone treatment for 3 months, the type 2 diabetes patients with PPAR-γ2 rs1801282 CG genotypes significantly showed higher differential values of postprandial plasma glucose and serum triglyceride compared with those with rs1801282 CC genotype. The patients with PTPRD rs17584499 CT+TT genotypes showed significantly lower differential value of postprandial plasma glucose compared to those with rs17584499 CC genotype. Conclusion: Diabetes risk alleles in PPAR-γ2 (rs1801282) and PTPRD (rs17584499) are associated with pioglitazone therapeutic efficacy.
Background and ObjectivesApproximately 10–15% of children with Kawasaki disease (KD) do not respond to initial intravenous immunoglobulin (IVIG) and have higher risk for coronary artery lesion (CAL). The aim of this study was to identify predictive factors from laboratory findings in patients who do not respond to IVIG treatment and develop CAL from KD.MethodsWe retrospectively collected nationwide multicenter data from the Korean Society of Kawasaki Disease and included 5,151 patients with KD between 2012 and 2014 from 38 hospitals.ResultsAmong 5,151 patients with KD, 524 patients belonged to the IVIG-resistant group. The patients in the IVIG-resistant group had a significantly higher serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level (1,573.91±3,166.46 vs. 940.62±2,326.10 pg/mL; p<0.001) and a higher percentage of polymorphonuclear neutrophils (PMNs) (70.89±15.75% vs. 62.38±32.94%; p<0.001). Multivariate logistic regression analyses revealed that significantly increased PMN, NT-proBNP, C-reactive protein (CRP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were the predictors of IVIG resistance (p<0.05). Multivariate logistic regression analyses also showed that only CRP was associated with the risk of CAL (p<0.01), while PMN, NT-proBNP, AST, and ALT were not.ConclusionsElevated PMN, serum NT-proBNP, CRP, AST, and ALT levels are significantly associated with IVIG resistance in patients with KD. Moreover, serum CRP is significantly increased in patients with KD with CAL.
Background and ObjectivesThis was a multicenter study to evaluate the usefulness of the tumor necrosis factor-alpha (TNF-α) blocker infliximab for treatment of Korean pediatric patients with refractory Kawasaki disease (KD).Subjects and MethodsData from 16 patients throughout Korea who were diagnosed with refractory KD and received infliximab were collected retrospectively.ResultsComplete response to therapy with cessation of fever occurred in 13 of 16 patients. C-reactive protein (CRP) concentrations decreased following infliximab infusion in all 14 patients in whom it was measured before and after treatment. There were no infusion reactions or complications associated with infliximab except in 1 case with acute hepatitis occurring during treatment followed by calculous cholecystitis 4 months later. Fifteen patients had coronary artery (CA) abnormalities before infliximab therapy. Three had transient mild dilatation and 9 had CA aneurysms, with subsequent normalization in 4 patients, persistent mild dilatation in 3, persistent aneurysm in 2, and there were 3 cases (2 with CA aneurysm, 1 with mild CA dilatation) without follow-up echocardiography.ConclusionThe results of this study suggest that infliximab may be useful in the treatment of refractory KD, and it appears that there is no significant further progression of CA lesions developing after infliximab treatment. Multicenter trials with larger numbers of patients and long-term follow-up are necessary to assess the clinical efficacy and safety of infliximab in refractory KD.
Kawasaki disease (KD) is the most common cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) is the standard therapy for KD, but more than 10% of KD patients do not respond to IVIG and are at high risk for the development of coronary artery lesions (CALs). To identify clinical and genetic risk factors associated with CAL development and IVIG nonresponsiveness, this study analyzed the clinical data for 478 Korean KD patients. Multivariate logistic regression analysis showed that incomplete KD, IVIG nonresponse, fever duration of 7 days or longer, and the 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. The risk of CAL formation was synergistically increased by the addition of individual risk factors, particularly the genetic variant in the PELI1 gene. Multivariate analysis also showed that a serum albumin level of 3.6 g/dl or lower was significantly associated with nonresponsiveness to IVIG [OR, 2.76; 95% confidence interval (CI), 1.34-5.68; P = 0.006]. Conclusively, incomplete KD, IVIG nonresponsiveness, long febrile days, and the rs7604693 genetic variant in the PELI1 gene are major risk factors for the development of CALs, whereas low serum albumin concentration is an independent risk factor for IVIG nonresponsiveness.
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