Association of an IGHV3-66 gene variant with Kawasaki disease.

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

Identification of SAMD9L as a susceptibility locus for intravenous immunoglobulin resistance in Kawasaki disease by genome-wide association analysis.

Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10-20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P = 1.39 × 10-5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P = 5.30 × 10-6). These results provide new insights into the mechanism of IVIG response in KD.

Association of the IL16 Asn1147Lys polymorphism with intravenous immunoglobulin resistance in Kawasaki disease.

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.

The Risk Prediction of Coronary Artery Lesions through the Novel Hematological Z-Values in 4 Chronological Age Subgroups of Kawasaki Disease.

Background and Objectives: Most cases of Kawasaki disease (KD) occur between the ages of 6 months and 5 years. Differences in immunological reaction and CAL (coronary artery lesion) by the age subgroups classified according to the prevalence of KD and those particularly in the earlier life of KD should be investigated. Materials and Methods: The laboratory data of 223 infantile and 681 non-infantile KD cases from 2003 to 2018 at Korea University Hospital were retrospectively analyzed. Patients with KD were divided into infants and non-infants and further subdivided into four subgroups by age. The age-adjusted Z-values were compared among the subgroups. Febrile controls were identified as patients with fever for >5 days and who showed some of the KD symptoms. Results: IVIG (intravenous immunoglobulin) resistance at the age of 6 months or less was significantly lower than that at the ages of 7-12 months and 13-60 months (respectively, p < 0.05). The significant risk factors for CAL in total KD patients were age, incomplete KD, post-IVIG fever, IVIG resistance, convalescent Z-eosinophil, and subacute platelet (p < 0.05). The significant risk factors for CAL at the age of 6 months or less were IVIG resistance, acute Z-neutrophil, subacute Z-neutrophil, subacute NLR (neutrophil to lymphocyte ratio), and subacute platelet (respectively, p < 0.05). Conclusion: Younger age and incomplete presentation in KD can be independent risk factors for CAL. The immune reactions of KD at a younger age are more tolerated compared with those at older ages during the acute phase. The immune response at the age of 6 months or less showed immune tolerance in terms of incomplete presentation and IVIG responsiveness. The risk factors such as IVIG resistance, subacute platelet, subacute NLR, and acute or subacute Z-neutrophil at the age of 6 months or less can be very useful parameters to predict CAL in young, incomplete KD.

Identification of the TIFAB Gene as a Susceptibility Locus for Coronary Artery Aneurysm in Patients with Kawasaki Disease.

Kawasaki disease (KD) is a self-limiting systemic vasculitis of unknown etiology. KD is often complicated by coronary artery aneurysms (CAAs), which develop in about 20-25% of untreated children and 3-5% of children treated with intravenous immunoglobulin therapy. To identify the risk loci for CAA susceptibility in patients with KD, we performed a genome-wide association study (GWAS) using our previous Illumina HumanOmni1-Quad BeadChip data (296 KD patients) and a new replication study in an independent sample set (713 KD patients) by grouping KD patients without CAA (control) versus KD patients with extremely large aneurysms (diameter ≥ 5 mm) (case). Among 44 candidate single -nucleotide polymorphisms (SNPs) selected from the initial GWAS data (33 cases vs. 215 controls), a SNP (rs899162) located 7 kb upstream of the TIFAB gene on chromosome five was replicated in an independent sample (12 cases vs. 532 controls). In the combined analysis (45 cases vs. 747 controls), the SNP (rs899162) showed a highly significant association with CAA formation (diameter ≥ 5 mm) in patients with KD (odds ratio = 3.20, 95% confidence interval = 2.02-5.05, Pcombined = 1.95 × 10-7). These results indicate that the TIFAB gene may act as a CAA susceptibility locus in patients with KD.

Chronological Echocardiographic Changes in Healthy Term Neonates within Postnatal 72 Hours Using Doppler Studies.

BACKGROUND: This study evaluated echocardiographic changes in full-term healthy neonates during early transitional period from postnatal 0-72 hours at 12-hour intervals by echocardiography. METHODS: This was a prospective, observational, and longitudinal single-center cohort study. Morphometric, functional, systolic, diastolic, and tissue Doppler imaging (TDI) parameters (patent ductus arteriosus [PDA], aorta, superior vena cava [SVC], stroke volume [SV], cardiac output [CO], cardiac index [CI], early diastolic flow velocity [E], late diastolic flow velocity [A], early filling in TDI [E'], peak systolic annular velocity in TDI [S'], late velocity peak in TDI [A'], and myocardial performance index [MPI]) were evaluated in left ventricle (LV) and right ventricle (RV) with 56 newborns. RESULTS: Sizes and peak velocities of PDA before postnatal 24 hours were significantly changed than those after postnatal 24 hours. Aortic velocity time integral (VTI), systolic blood pressure (BP), LV SV/kg, LV CO/kg, LV CI, and SVC flow/LV CO before 24 hours showed significantly changes than those after 24 hours. Also, LV and RV MPI before 24 hours were significantly higher than those after 24 hours. LV E/E' was significantly higher than RV E/E'. CONCLUSION: Postnatal 24 hours is critical time for hemodynamic closure of PDA because aortic VTI, systolic BP, LV SV, LV CO, LV CI, and SVC flow/LV CO showed simultaneously significant changes after 24 hours at the same time as 24 hours of physiological closure of PDA. Chronological and dramatic changes of systolic, diastolic, and TDI parameters during early postnatal period can be used to compile normal baseline data of healthy full-term neonates.

A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease.

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.

Impact of time to treatment of oseltamivir on influenza hospitalization cost among Korean children.

BACKGROUND: Although oseltamivir is a common influenza treatment, there is a lack of data on the economic benefits of timely oseltamivir treatment. METHODS: From February 2004 through June 2007, 116 hospitalized children ≤ 15 years of age with laboratory-confirmed influenza who received oseltamivir were identified via retrospective medical chart review. Demographic, clinical, and cost data were abstracted and multivariate linear regression was used to assess the association between oseltamivir time to treatment and treatment-related costs among hospitalized children with laboratory-confirmed influenza. RESULTS: Overall, 28% (n = 33) of patients were treated with oseltamivir ≥ day 3 of admission. Rapid influenza diagnostic test was used in a significantly lower proportion of patients treated with oseltamivir ≥ day 3 of admission compared with those who received oseltamivir earlier. On multivariate linear regression, initiation of oseltamivir ≥ day 3 of admission was associated with a 60.84% increase (95%CI: 32.59-95.11) in treatment-related hospital costs, compared with initiation on admission. CONCLUSION: Delayed initiation of oseltamivir was found to be associated with increased treatment-related hospital costs among children hospitalized with laboratory-confirmed influenza.

Nationwide survey of coronary aneurysms with diameter >6 mm in Kawasaki disease in Korea.

BACKGROUND: We investigated the course of coronary aneurysm with diameter > 6 mm in Kawasaki disease (KD), as well as related therapeutic trends and prognosis in Korea. METHODS: A nationwide questionnaire survey was carried out in 77 hospitals, to investigate, retrospectively, patients with KD who had coronary aneurysms with a diameter > 6 mm between 1990 and 2011. RESULTS: The median age of onset was 3 years (range, 2 months-16 years) in a total of 239 patients. During the acute stage of KD, most patients received i.v. immunoglobulins and aspirin. In addition, 27 patients received steroid therapy. In the current study, the mean coronary aneurysm size was 8.7 ± 3.2 mm (range, 6-21 mm). Twenty-two patients underwent interventional catheterization. Procedures included percutaneous transluminal coronary balloon angioplasty (n = 10), stent placement (n = 9), and percutaneous transluminal coronary rotational ablation (n = 3). Fourteen patients underwent coronary artery bypass graft surgery. Of the 239 patients who had coronary aneurysms with diameter > 6 mm, 13 (5.4%) presented with findings suggestive of myocardial infarction. Five patients died during the follow-up period. CONCLUSIONS: Severe stenosis or occlusion of the coronary artery may occur in some patients who develop coronary aneurysms with diameter > 6 mm; early management such as coronary interventions or surgery should be considered in such cases.

Common variants in the CRP promoter are associated with a high C-reactive protein level in Kawasaki disease.

Kawasaki disease (KD) is an acute self-limiting form of vasculitis that afflicts infants and children and manifests as fever and signs of mucocutaneous inflammation. Children with KD show various laboratory inflammatory abnormalities, such as elevations in their white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). We here performed a genome-wide association study (GWAS) of 178 KD patients to identify the genetic loci that influence 10 important KD laboratory markers: WBC count, neutrophil count, platelet count, CRP, ESR, hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication (p < 1 × 10(-5)). Of these, only 2 SNPs (rs12068753 and rs4786091) demonstrated a significant association with the CRP level in replication study of 473 KD patients (p < 0.05). The SNP located at the CRP locus (rs12068753) demonstrated the most significant association with CRP in KD patients (beta = 4.73 and p = 1.20 × 10(-6) according to the stage 1 GWAS; beta = 3.65 and p = 1.35 × 10(-8) according to the replication study; beta = 3.97 and p = 1.11 × 10(-13) according to combined analysis) and explained 8.1% of the phenotypic variation observed. However, this SNP did not demonstrate any significant association with CRP in the general population (beta = 0.37 and p = 0.1732) and only explained 0.1% of the phenotypic variation in this instance. Furthermore, rs12068753 did not affect the development of coronary artery lesions or intravenous immunoglobulin resistance in KD patients. These results indicate that common variants in the CRP promoter can play an important role in the CRP levels in KD.

Effect of Preoperative Lipidemic Control on Retear Rates After Rotator Cuff Repair in Patients With Hyperlipidemia.

BACKGROUND: In patients with hyperlipidemia, the risk of retear increases after rotator cuff repair (RCR). In particular, it has been reported that preoperative low-density lipoprotein cholesterol (LDL-C) level affects cuff integrity. However, there are no studies assessing whether lipidemic control affects cuff healing. PURPOSE: To evaluate the effect of preoperative lipidemic control on cuff integrity after arthroscopic RCR across cardiovascular disease risk groups in patients with hyperlipidemia. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The authors retrospectively reviewed the charts of patients with hyperlipidemia who underwent arthroscopic double-row suture bridge RCR between 2014 and 2019. The included patients had LDL-C tested within 1 month before surgery. Magnetic resonance imaging was conducted 6 months after surgery to evaluate the integrity of the repaired cuff tendon. Patients were divided into groups of low, moderate, high, and very high risk according to the 4th Korean Dyslipidemia Guidelines. On the basis of the target LDL-C set in each risk group, patients were categorized into 2 groups: group C (controlled hyperlipidemia, less than target LDL-C) and group U (uncontrolled hyperlipidemia, target LDL-C or greater). The correlation between serum lipid profile, lipidemic control, and post-RCR integrity was evaluated. RESULTS: A total of 148 patients were analyzed, 51 in group U and 97 in group C. The retear rate was significantly higher in group U than in group C (23/51 [45.1%] vs 18/97 [18.6%], respectively; P = .001). The proportion of group U was significantly higher in the retear group than in the healing group (56.1% vs 26.2%; P = .001). In addition, the proportions of patients with uncontrolled diabetes mellitus (DM) (19.5% vs 3.7%; P = .002) and mediolateral (2.6 ± 1.2 cm vs 1.7 ± 1.1 cm; P < .001) and anteroposterior (2.2 ± 1.1 cm vs 1.6 ± 0.8 cm; P = .003) tear sizes were significantly different between the retear and healing groups, respectively. No significant difference in serum lipid profile, including LDL-C level (119.6 ± 31.3 vs 116.7 ± 37.2; P = .650), was observed between the retear and healing groups. Multivariate regression analysis identified uncontrolled hyperlipidemia (OR, 4.005; P = .001), uncontrolled DM (OR, 5.096; P = .022), and mediolateral tear size (OR, 1.764; P = .002) as independent risk factors for retear. The 2.0-cm mediolateral size cutoff and the 3 independent risk factors had significant associations with retear. CONCLUSION: Poor preoperative lipidemic control was significantly associated with poor healing after RCR. In addition to large mediolateral tear size, uncontrolled hyperlipidemia and DM were significant risk factors for retear. Moreover, poor lipidemic control compared with the recommended target level before surgery was more correlated with an increased retear rate than a preoperative LDL-C level.

Survival and Risk Factors for Mortality in Infants With Congenital Heart Disease in South Korea.

BACKGROUND/AIM: The survival of patients with congenital heart disease (CHD) has dramatically improved over recent decades. However, a disparity exists depending on the country and medical system. This study aimed to analyze the survival of infants with CHD until the age of 18 years using large-scale population data in South Korea and investigate the effect of neonatal conditions at birth. PATIENTS AND METHODS: We retrospectively extracted the Korean National Health Insurance Service claims data from January 2002 to December 2020. We included patients diagnosed with CHD who were less than one year of age. The follow-up duration was until their death or until they were censored before the age of 18 years. The CHD lesions were classified hierarchically (conotruncal, severe non-conotruncal, coarctation of the aorta, ventricular septal defect, atrial septal defect, and others). Several neonatal conditions were adopted as risk factors. RESULTS: Overall, 127,958 infants had been diagnosed with CHD and 2,275 died before the age of 18 years. The survival rate of infants with CHD during childhood was 97.9%. The highest childhood mortality rate was associated with non-conotruncal defects (19.7%), followed by conotruncal defects (10.2%). The significant risk factors for childhood mortality were complex CHD, pulmonary hypertension, birth asphyxia, small for gestational age, respiratory distress, pulmonary hemorrhage, bronchopulmonary dysplasia, and convulsions. CONCLUSION: The survival of infants with CHD has been favorable in South Korea. Several neonatal conditions are risk factors for childhood mortality. Individualized risk assessment and optimal treatment strategies may help improve their survival rate.

Sex-Specific Susceptibility Loci Associated With Coronary Artery Aneurysms in Patients With Kawasaki Disease.

BACKGROUND AND OBJECTIVES: Kawasaki disease (KD) is an acute vasculitis that primarily affects children under age 5 years. Approximately 20-25% of untreated children with KD and 3-5% of those treated with intravenous immunoglobulin therapy develop coronary artery aneurysms (CAAs). The prevalence of CAAs is much higher in male than in female patients with KD, but the underlying factors contributing to susceptibility to CAAs in patients with KD remain unclear. This study aimed to identify sex-specific susceptibility loci associated with CAAs in KD patients. METHODS: A sex-stratified genome-wide association study (GWAS) was performed using previously obtained GWAS data from 296 KD patients and a new replication study in an independent set of 976 KD patients by comparing KD patients without CAA (controls) and KD patients with aneurysms (internal diameter ≥5 mm) (cases). RESULTS: Six male-specific susceptibility loci, PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ (odds ratios [ORs], 2.25-9.98; p=0.00204-1.96×10-6), and 2 female-specific susceptibility loci, SMAD3 (OR, 4.59; p=0.00016) and IL1RAPL1 (OR, 4.35; p=0.00026), were significantly associated with CAAs in patients with KD. In addition, the numbers of CAA risk alleles additively contributed to the development of CAAs in patients with KD. CONCLUSIONS: A sex-stratified GWAS identified 6 male-specific (PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ) and 2 female-specific (SMAD3 and IL1RAPL1) CAA susceptibility loci in patients with KD.

Clinical manifestations of respiratory adenoviral infection among hospitalized children in Korea.

BACKGROUND: The objective of our study was to understand the epidemiological and clinical features of respiratory adenoviral infections among children at a single institution over the course of several years. METHODS: From January 2005 to April 2009, 1836 children (≤15 years old) who had been admitted to Korea University Ansan Hospital were tested for acute respiratory infection. The patients who were positive for an adenovirus infection were enrolled in this study, and their medical records were retrospectively reviewed. RESULTS: Adenoviruses were isolated from 310 patients. The male to female ratio was 1.6:1 and mean age was 32 ± 24 months. Children under 5 years of age had the highest prevalence. In 2007, adenovirus infections occurred endemically throughout the year. The clinical diagnoses were primarily upper respiratory tract infections (45.4%), lower respiratory tract infections (48.1%), and neurologic disease (5.2%). Associated symptoms, signs and laboratory findings included fever (91.9%), cough (83.9%), pharyngeal injection (62.3%), rale (32.6%) and elevated C-reactive protein (93.9%). The most common radiologic findings were perihilar and peribronchial infiltrates (42.6%). Co-infections were observed in 29 cases. The mean durations of hospitalization and fever were 6.2 ± 6.5 and 4.8 ± 3.1 days, respectively. The lengths of hospitalization were similar for patients admitted for upper respiratory tract infections with severe morbidity and those admitted for lower respiratory tract infections. No children in the study died. CONCLUSION: Our study demonstrates that respiratory adenovirus infections are an important cause of hospitalization in young children, and contribute to a significant morbidity.

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

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

Assessment of risk factors for Korean children with Kawasaki disease.

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.

Variations in the number of CCL3L1 gene copies and Kawasaki disease in Korean children.

High-dose intravenous immunoglobulin (IVIG) therapy is the highly effective and standard treatment for Kawasaki disease (KD). However, ~20 % of KD patients have persistent fever or recurrence of fever after the initial IVIG treatment, which increases the risk for coronary artery lesions (CALs). Furthermore, the mechanism of IVIG resistance in KD patients still is unknown. The number of CC chemokine ligand 3-like 1 (CCL3L1) gene copies is reported to be associated with KD and IVIG resistance in Japanese patients. In addition, the authors observed significant upregulation of the CCL3L1 gene expression after in vitro immunoglobulin treatment in B cell lines derived from KD patients. Therefore, this study of 459 KD patients and 496 healthy control subjects tested whether the number of CCL3L1 gene copies is associated with a risk of KD, CALs, and/or IVIG resistance in Korean KD patients. However, the number of CCL3L1 gene copies was not associated with KD (P = 0.18), CAL formation (P = 0.062), or the IVIG resistance (P = 0.90). Therefore, the results indicate that the number of CCL3L1 gene copies does not have a role in susceptibility to KD or CALs nor with IVIG resistance in Korean KD patients.

A genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for Kawasaki disease.

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.

Cellular and RAS changes in the hearts of young obese rats.

Obesity during childhood increases the risk of cardiac disease, hypertension, and other complications in adulthood. We investigated the cellular and renin-angiotensin system changes of the heart in obese young rats. We used Sprague-Dawley rats and early obesity was induced by overfeeding through adjusting the number of male pups per dam during the first 28 days of life. The body weight, heart weight, blood pressure, serum glucose, and blood pressure were assessed and we performed echocardiography, proliferating cell nuclear antigen (PCNA); assessment, apoptosis and Masson's trichrome staining, and Western blotting and the results were compared between the normal litter (NL, control) and the small litter (SL, obesity). There were no differences in blood pressure and serum glucose, but the body weight increased 61.2% and the interventricular septal thickness in diastole on the echocardiography was increased in the SL. There was hyperplasia of the PCNA cells and apoptotic cells without cellular hypertrophy or change of the amount of collagen in the SL. On Western blotting, rennin, and angiotensin II type 2 receptor (AT2R) were increased without a change of angiotensin II type 1 receptor (AT1R) in the SL. Early obesity caused echocardiographically detected septal hypertrophy and an increase of cellular turnover. Renin and AT2R were upregulated without a change of AT1R and the increase of AT2R was regarded as a cardioprotective effect against the pathologic conditions caused by the early obesity.

Identification of rare coding variants associated with Kawasaki disease by whole exome sequencing.

Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18 to 4.41; p = 0.0027-0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89 to 37.3; p = 0.0058-0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.