PCNA Ser46-Leu47 residues are crucial in preserving genomic integrity.

Proliferating cell nuclear antigen (PCNA) is a maestro of DNA replication. PCNA forms a homotrimer and interacts with various proteins, such as DNA polymerases, DNA ligase I (LIG1), and flap endonuclease 1 (FEN1) for faithful DNA replication. Here, we identify the crucial role of Ser46-Leu47 residues of PCNA in maintaining genomic integrity using in vitro, and cell-based assays and structural prediction. The predicted PCNAΔSL47 structure shows the potential distortion of the central loop and reduced hydrophobicity. PCNAΔSL47 shows a defective interaction with PCNAWT leading to defects in homo-trimerization in vitro. PCNAΔSL47 is defective in the FEN1 and LIG1 interaction. PCNA ubiquitination and DNA-RNA hybrid processing are defective in PCNAΔSL47-expressing cells. Accordingly, PCNAΔSL47-expressing cells exhibit an increased number of single-stranded DNA gaps and higher levels of γH2AX, and sensitivity to DNA-damaging agents, highlighting the importance of PCNA Ser46-Leu47 residues in maintaining genomic integrity.

Learning curve for single-port robot-assisted rectal cancer surgery.

Purpose: We analyzed the learning curve of single-port robotic (SPR)-assisted rectal cancer surgery. Methods: Fifty-seven consecutive SPR-assisted rectal cancer surgery cases performed by the same surgeon were considered in surgical interventions for rectal cancer. Total operation time (OT), docking time (DT), and surgeon console time (SCT) measured during surgery were used to parametrize the learning curve. The parameters representing the learning curve were evaluated using the cumulative sum (CUSUM). Results: The mean value of total OT was 241.8 ± 91.7 minutes, the mean value of DT was 20.6 ± 19.1 minutes, and the mean value of SCT was 135.9 ± 66.7 minutes. The learning curve was divided into phase 1 (initial 16 cases), phase 2 (second 16 cases), and phase 3 (subsequent 25 cases). The peak on the CUSUM graph occurred in the 21st case. The longest OT among phases was in phase 2. Complications were most frequent in phase 2. However, complications of Clavien-Dindo (CD) grade IIIb were most frequent in phase 3 with 2 patients. The most common complications were fluid collection and urinary retention (7 patients each). Complications of CD grade IIIb required one stomal revision due to stoma obstruction and one irrigation and loop ileostomy due to anastomosis leakage. Conclusion: Improvement in surgical performance of SPR assisted rectal cancer operation was achieved after 21 cases. The three phases identified in the cumulative sum analysis showed a significant decrease in operative time after the middle stage of the learning curve without an increase in the complication rate.

Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia.

Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI-induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI-mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML.

Neuropeptide Y: a potential theranostic biomarker for diabetic peripheral neuropathy in patients with type-2 diabetes.

BACKGROUND: Diabetic peripheral neuropathy (DPN), the most common microvascular complication of type-2 diabetes mellitus (T2DM), results in nontraumatic lower-limb amputations. When DPN is not detected early, disease progression is irreversible. Thus, biomarkers for diagnosing DPN are needed. METHODS: We analyzed three data sets of T2DM DPN: two for mouse models (GSE70852 and GSE34889) and one for a human model (GSE24290). We found common differentially expressed genes (DEGs) in the two mouse data sets and validated them in the human data set. To identify the phenotypic function of the DEGs, we overexpressed them in zebrafish embryos. Clinical information and serum samples of T2DM patients with and without DPN were obtained from the Korea Biobank Network. To assess the plausibility of DEGs as biomarkers of DPN, we performed an enzyme-linked immunosorbent assay. RESULTS: Among the DEGs, only NPY and SLPI were validated in the human data set. As npy is conserved in zebrafish, its mRNA was injected into zebrafish embryos, and it was observed that the branches of the central nervous system became thicker and the number of dendritic branches increased. Baseline characteristics between T2DM patients with and without DPN did not differ, except for the sex ratio. The mean serum NPY level was higher in T2DM patients with DPN than in those without DPN (p = 0.0328), whereas serum SLPI levels did not differ (p = 0.9651). CONCLUSION: In the pathogenesis of DPN, NPY may play a protective role in the peripheral nervous system and may be useful as a biomarker for detecting T2DM DPN.

SOCS3 is Related to Cell Proliferation in Neuronal Tissue: An Integrated Analysis of Bioinformatics and Experiments.

Glioma is the most common primary malignant tumor that occurs in the central nervous system. Gliomas are subdivided according to a combination of microscopic morphological, molecular, and genetic factors. Glioblastoma (GBM) is the most aggressive malignant tumor; however, efficient therapies or specific target molecules for GBM have not been developed. We accessed RNA-seq and clinical data from The Cancer Genome Atlas, the Chinese Glioma Genome Atlas, and the GSE16011 dataset, and identified differentially expressed genes (DEGs) that were common to both GBM and lower-grade glioma (LGG) in three independent cohorts. The biological functions of common DEGs were examined using NetworkAnalyst. To evaluate the prognostic performance of common DEGs, we performed Kaplan-Meier and Cox regression analyses. We investigated the function of SOCS3 in the central nervous system using three GBM cell lines as well as zebrafish embryos. There were 168 upregulated genes and 50 downregulated genes that were commom to both GBM and LGG. Through survival analyses, we found that SOCS3 was the only prognostic gene in all cohorts. Inhibition of SOCS3 using siRNA decreased the proliferation of GBM cell lines. We also found that the zebrafish ortholog, socs3b, was associated with brain development through the regulation of cell proliferation in neuronal tissue. While additional mechanistic studies are necessary, our results suggest that SOCS3 is an important biomarker for glioma and that SOCS3 is related to the proliferation of neuronal tissue.

Large-scale generation and phenotypic characterization of zebrafish CRISPR mutants of DNA repair genes.

A systematic knowledge of the roles of DNA repair genes at the level of the organism has been limited due to the lack of appropriate experimental approaches using animal model systems. Zebrafish has become a powerful vertebrate genetic model system with availability due to the ease of genome editing and large-scale phenotype screening. Here, we generated zebrafish mutants for 32 DNA repair and replication genes through multiplexed CRISPR/Cas9-mediated mutagenesis. Large-scale phenotypic characterization of our mutant collection revealed that three genes (atad5a, ddb1, pcna) are essential for proper embryonic development and hematopoiesis; seven genes (apex1, atrip, ino80, mre11a, shfm1, telo2, wrn) are required for growth and development during juvenile stage and six genes (blm, brca2, fanci, rad51, rad54l, rtel1) play critical roles in sex development. Furthermore, mutation in six genes (atad5a, brca2, polk, rad51, shfm1, xrcc1) displayed hypersensitivity to DNA damage agents. Our zebrafish mutant collection provides a unique resource for understanding of the roles of DNA repair genes at the organismal level.

FRZB as a key molecule in abdominal aortic aneurysm progression affecting vascular integrity.

Abdominal aortic aneurysm (AAA), when ruptured, results in high mortality. The identification of molecular pathways involved in AAA progression is required to improve AAA prognosis. The aim of the present study was to assess the key genes for the progression of AAA and their functional role. Genomic and clinical data of three independent cohorts were downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) (GSE57691, GSE7084, and GSE98278). To develop AAA diagnosis and progression-related differentially expressed genes (DEGs), we used a significance analysis of microarray (SAM). Spearman correlation test and gene set analysis were performed to identify potential enriched pathways for DEGs. Only the Frizzled-related protein (FRZB) gene and chromosome 1 open reading frame 24 (C1orf24) exhibited significant down-regulation in all analyses. With FRZB, the pathways were associated with RHO GTPase and elastin fiber formation. With C1orf24, the pathways were elastic fiber formation, extracellular matrix organization, and cell-cell communication. Since only FRZB was evolutionally conserved in the vertebrates, function of FRZB was validated using zebrafish embryos. Knockdown of frzb remarkably reduced vascular integrity in zebrafish embryos. We believe that FRZB is a key gene involved in AAA initiation and progression affecting vascular integrity.

AML poor prognosis factor, TPD52, is associated with the maintenance of haematopoietic stem cells through regulation of cell proliferation.

Acute myeloid leukaemia (AML) is a blood cancer where undifferentiated myeloid cells are increased in the bone marrow and peripheral blood. As AML is dangerous and shows poor prognosis, many researchers categorised the relevant cytogenetic factors according to risk and prognosis. However, the specific reasons for poor cytogenetic factors remain unknown. We analysed a large data set from AML patients and found that TPD52 expression is elevated in patient groups with poor cytogenetic factors. As the amino acid sequence of TPD52 is evolutionally conserved in vertebrates, zebrafish embryos were used to investigate the function of TPD52. Since myeloid-biased haematopoietic stem cells (HSCs) are relevant to AML, the function of TPD52 in the development of HSCs was investigated. We determined that the zebrafish paralog, tpd52, is important for the maintenance of HSCs through regulation of cell proliferation. As tpd52 is linked to cell proliferation in zebrafish embryos, the proliferation-related gene, CD59, was correlated to TPD52 in every AML cohort with a high correlation coefficient. We suggest that TPD52 can be a novel therapeutic target for AML patients with poor cytogenetic factors. Additionally, more studies between TPD52 and CD59 will further increase the value of TPD52 as a novel target.

Haematopoietic stem cell-dependent Notch transcription is mediated by p53 through the Histone chaperone Supt16h.

Haematopoietic stem and progenitor cells (HSPCs) have been the focus of developmental and regenerative studies, yet our understanding of the signalling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the Facilitates chromatin transcription (FACT) complex, is required for HSPC formation. Zebrafish supt16h mutants express reduced levels of Notch-signalling components, genes essential for HSPC development, due to abrogated transcription. Whereas global chromatin accessibility in supt16h mutants is not substantially altered, we observe a specific increase in p53 accessibility, causing an accumulation of p53. We further demonstrate that p53 influences expression of the Polycomb-group protein PHC1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues the loss of both Notch and HSPC phenotypes in supt16h mutants. Our results highlight a relationship between supt16h, p53 and phc1 to specify HSPCs via modulation of Notch signalling.

LRRC17 Is Linked to Prognosis of Ovarian Cancer Through a p53-dependent Anti-apoptotic Function.

BACKGROUND/AIM: Since pathways involving LRRC17 are related to the survival of patients with various cancers, we analyzed LRRC17 as a prognostic gene in serous ovarian cancer. MATERIALS AND METHODS: Data were collected from Gene Expression Omnibus (GSE9891, GSE13876, and GSE26712) and The Cancer Genome Atlas (TCGA). We performed survival analyses using C statistics, area under the curve, survival plot with optimal cutoff level, and cox proportional regression. Zebrafish embryos were used as an in vivo model. RESULTS: The prognosis of patients with high LRRC17 expression was poorer than that of patients with low LRRC17 expression. Multivariate regression analysis showed that LRRC17 expression, age, and stage were independently related with survival. Knockdown of lrrc17 reduced survival rate and delayed development in zebrafish embryos. We also found that lrrc17 is important for cell viability by protecting from p53-dependent apoptosis. CONCLUSION: LRRC17 could be a prognostic gene in ovarian cancer as it regulates cancer cell viability through the p53 pathway.

Role of kif2c, A Gene Related to ALL Relapse, in Embryonic Hematopoiesis in Zebrafish.

Relapse of acute lymphoblastic leukemia (ALL) is dangerous and it worsens the prognosis of patients; however, prognostic markers or therapeutic targets for ALL remain unknown. In the present study, using databases such as TARGET, GSE60926 and GSE28460, we determined that KIF2C and its binding partner, KIF18B are overexpressed in patients with relapsed ALL compared to that in patients diagnosed with ALL for the first time. As 50% of the residues are exactly the same and the signature domain of KIF2C is highly conserved between human and zebrafish, we used zebrafish embryos as a model to investigate the function of kif2c in vivo. We determined that kif2c is necessary for lymphopoiesis in zebrafish embryos. Additionally, we observed that kif2c is not related to differentiation of HSCs; however, it is important for the maintenance of HSCs as it provides survival signals to HSCs. These results imply that the ALL relapse-related gene KIF2C is linked to the survival of HSCs. In conclusion, we suggest that KIF2C can serve as a novel therapeutic target for relapsed ALL.

FAM213A is linked to prognostic significance in acute myeloid leukemia through regulation of oxidative stress and myelopoiesis.

Accurate prediction of malignancies is important in choosing therapeutic strategies. Although there are many genetic and cytogenetic prognostic factors for acute myeloid leukemia (AML), prognosis is difficult to predict because of the heterogeneity of AML. Prognostic factors, including messenger RNA (mRNA) expression, have been determined for other malignancies, but not for AML. A total of 402 patients from The Cancer Genome Atlas, GSE12417 (GPL96, 97), and GSE12417 (GPL570) were included in this study. In Kaplan-Meier curve analyses, high expression of family with sequence similarity 213 member A (FAM213A), which activates antioxidant proteins, was associated with worse prognosis of AML. Similar to the results of the survival curve, C-indices and area under the curve values were high. Current prognostic factors of AML, unlike those of other cancers, do not take mRNA expression into consideration. Thus, the development of mRNA-based prognostic factors would be beneficial for accurate prediction of the survival of AML patients. Additionally, in vivo validation using zebrafish revealed that fam213a is important for myelopoiesis at the developmental stage and is a negative regulator of the p53 tumor suppressor gene. The findings implicate fam213a as a novel prognostic factor for AML patients.

Long-term Oncologic Outcome of Postoperative Complications After Colorectal Cancer Surgery.

PURPOSE: The impact of postoperative complications on long-term oncologic outcome after radical colorectal cancer surgery is controversial. The aim of this study was to examine the risk factors and oncologic outcomes of surgery-related postoperative complication groups. METHODS: From January 2010 to December 2010, 310 patients experienced surgery-related postoperative complications after radical colorectal cancer surgery. These stage I-III patients were classified into 2 subgroups, minor (grades I, II) and major (grades III, IV) complication groups, according to extended Clavien-Dindo classification system criteria. Clinicopathologic differences between the 2 groups were analyzed to identify risk factors for major complications. The disease-free survival rates of surgery-related postoperative complication groups were also compared. RESULTS: Minor and major complication groups were stratified with 194 patients (62.6%) and 116 patients (37.4%), respectively. The risk factors influencing the major complication group were pathologic N category and operative method. The prognostic factors associated with disease-free survival were preoperative perforation, perineural invasion, tumor budding, and receiving neoadjuvant therapy. With a median follow-up period of 72.2 months, the 5-year disease-free survival rates were 84.4% in the minor group and 78.5% in the major group, but there was no statistical significance between the minor and major groups (P = 0.392). CONCLUSION: Advanced cancer and open surgery were identified as risk factors for increased surgery-related major complications after radical colorectal cancer surgery. However, severity of postoperative complications did not affect disease-free survival from colorectal cancer.

Dietary and Sentinel Factors Leading to Hemochromatosis.

Although hereditary hemochromatosis is associated with the mutation of genes involved in iron transport and metabolism, secondary hemochromatosis is due to external factors, such as intended or unintended iron overload, hemolysis-linked iron exposure or other stress-impaired iron metabolism. The present review addresses diet-linked etiologies of hemochromatosis and their pathogenesis in the network of genes and nutrients. Although the mechanistic association to diet-linked etiologies can be complicated, the stress sentinels are pivotally involved in the pathological processes of secondary hemochromatosis in response to iron excess and other external stresses. Moreover, the mutations in these sentineling pathway-linked genes increase susceptibility to secondary hemochromatosis. Thus, the crosstalk between nutrients and genes would verify the complex procedures in the clinical outcomes of secondary hemochromatosis and chronic complications, such as malignancy. All of this evidence provides crucial insights into comprehensive clinical or nutritional interventions for hemochromatosis.

Evaluation of the prognostic significances of γ-secretase genes in pancreatic cancer.

With the growing requirement for novel prognostic biomarkers for pancreatic cancer, many studies have focused on clinical and/or genomic variables. Although many studies have been performed, carbohydrate antigen 19-9 is the only biomarker in clinical use. Therefore, the present study examined whether γ-secretase genes, including presenilin (PSEN), nicastrin (NCSTN), presenilin enhancer protein 2 (PSENEN), and anterior pharynx-defective 1 (APH1-), could serve as prognostic factors for pancreatic cancer. The cohorts selected included >100 pancreatic cancer patients. Patient data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE21501). The prognostic roles of the γ-secretase genes were analyzed by several survival analysis methods. Among the γ-secretase genes, the prognosis tended to be worse in the 2 cohorts with increasing expression of PSEN1, APH1A, and PSENEN, while the remaining genes were the opposite in the 2 cohorts. Notably, although the patient characteristics were quite different, APH1A was statistically significantly associated with prognosis in the 2 cohorts. The hazard ratio of APH1A for overall survival was 1.598 (TCGA) and 2.724 (GSE21501). These results contribute to the study of γ-secretase in pancreatic cancer. We believe that γ-secretase, particularly APH1A, will be a new prognostic biomarker for pancreatic cancer.

Non-mutagenic Suppression of Enterocyte Ferroportin 1 by Chemical Ribosomal Inactivation via p38 Mitogen-activated Protein Kinase (MAPK)-mediated Regulation: EVIDENCE FOR ENVIRONMENTAL HEMOCHROMATOSIS.

Iron transfer across the basolateral membrane of an enterocyte into the circulation is the rate-limiting step in iron absorption and is regulated by various pathophysiological factors. Ferroportin (FPN), the only known mammalian iron exporter, transports iron from the basolateral surface of enterocytes, macrophages, and hepatocytes into the blood. Patients with genetic mutations in FPN or repeated blood transfusion develop hemochromatosis. In this study, non-mutagenic ribosomal inactivation was assessed as an etiological factor of FPN-associated hemochromatosis in enterocytes. Non-mutagenic chemical ribosomal inactivation disrupted iron homeostasis by regulating expression of the iron exporter FPN-1, leading to intracellular accumulation in enterocytes. Mechanistically, a xenobiotic insult stimulated the intracellular sentinel p38 MAPK signaling pathway, which was positively involved in FPN-1 suppression by ribosomal dysfunction. Moreover, ribosomal inactivation-induced iron accumulation in Caenorhabditis elegans as a simplified in vivo model for gut nutrition uptake was dependent on SEK-1, a p38 kinase activator, leading to suppression of FPN-1.1 expression and iron accumulation. In terms of gene regulation, ribosomal stress-activated p38 signaling down-regulated NRF2 and NF-κB, both of which were positive transcriptional regulators of FPN-1 transcription. This study provides molecular evidence for the modulation of iron bioavailability by ribosomal dysfunction as a potent etiological factor of non-mutagenic environmental hemochromatosis in the gut-to-blood axis.

Acquisition of Chemoresistance and Other Malignancy-related Features of Colorectal Cancer Cells Are Incremented by Ribosome-inactivating Stress.

Colorectal cancer (CRC) as an environmental disease is largely influenced by accumulated epithelial stress from diverse environmental causes. We are exposed to ribosome-related insults, including ribosome-inactivating stress (RIS), from the environment, dietary factors, and medicines, but their physiological impacts on the chemotherapy of CRC are not yet understood. Here we revealed the effects of RIS on chemosensitivity and other malignancy-related properties of CRC cells. First, RIS led to bidirectional inhibition of p53-macrophage inhibitory cytokine 1 (MIC-1)-mediated death responses in response to anticancer drugs by either enhancing ATF3-linked antiapoptotic signaling or intrinsically inhibiting MIC-1 and p53 expression, regardless of ATF3. Second, RIS enhanced the epithelial-mesenchymal transition and biogenesis of cancer stem-like cells in an ATF3-dependent manner. These findings indicate that gastrointestinal exposure to RIS interferes with the efficacy of chemotherapeutics, mechanistically implying that ATF3-linked malignancy and chemoresistance can be novel therapeutic targets for the treatment of environmentally aggravated cancers.

Recent incidence of congenital heart disease in neonatal care unit of secondary medical center: a single center study.

PURPOSE: With feasibility in the diagnoses of congenital heart disease (CHD) in the antenatal period, we suspect changes have occurred in its incidence. No data have been reported about the current incidence of simple forms of CHD in Korea. We have attempted to assess the recent incidence and characteristics of CHD in the neonatal care unit of a secondary referral medical center. METHODS: Medical records of 497 neonatal care unit patients who underwent echocardiography in the past 5 years were reviewed. Pre-term infants with patent ductus arteriosus and other transient, minimal lesions were excluded from this study. RESULTS: Although the number of inpatients remained stable, the incidence of simple forms of CHD showed a gradual decrease over the 5-year study period; a markedly low incidence of complex forms was seen as well. CHD was observed in 3.7% full-term and 6.8% pre-term infants. CHD was observed in 152 infants weighing >2,500 g (3.5% of corresponding birth weight infants); 65 weighing 1,000 to 2,500 g (9.3%); and 6 weighing <1,000 g (8.0%). The incidence of CHD was higher in the pre-term group and the low birth weight group than in each corresponding subgroup (P<0.001); however, the incidence of complex CHD in full-term neonates was high. The number of patients with extracardiac structural anomalies has also shown a gradual decrease every year for the past 5 years. CONCLUSION: Findings from our study suggest that the recent incidence and disease pattern of CHD might have changed for both complex and simple forms of CHD in Korea.

Establishment of secondary iron overloaded mouse model: evaluation of cardiac function and analysis according to iron concentration.

Periodic blood transfusion can lead to secondary iron overload in patients with hematologic and oncologic diseases. Iron overload can result in iron deposition in heart tissue, which decreases cardiac function and can ultimately lead to death due to dilated cardiomyopathy and cardiac failure. In this study, we established murine model of secondary iron overload, studied the changes in cardiac function with echocardiography, and examined the histopathologic changes. Three experimental groups of the six week-old C57/BL mice (H-2(b)) were injected intraperitoneally with 10 mg of iron dextran daily 5 days a week for 2, 4, and 6 weeks. Cumulative doses of iron for the three experimental groups were 100, 200, and 300 mg, while the control groups were injected with the same amounts of phosphate-buffered saline. We studied the cardiac function under anesthesia with echocardiography using a GE Vivid7 Dimension system. Plasma iron levels and liver iron contents were measured. The hearts and livers were harvested and stained with H&E and Perls Prussian blue for iron, and the levels of iron deposit were examined. We assessed the cardiac measurements after adjustment for weight. On echocardiography, thicknesses of the interventricular septum and posterior ventricular wall (PS) during diastole showed correlation with the amount of iron deposit (P < 0.01). End-diastolic volume showed dilatation of the left ventricle in the 300 mg group (P < 0.01). Changes in the fractional shortening were not statistically significant (P = 0.07). Plasma iron levels and liver iron contents were increased proportionally according to the amount of iron loaded. The histopathologic findings of PS and liver showed higher grade of iron deposit proportional to the cumulated iron dose. In this study, we present an animal model which helps understand the cardiac function changes in patients with secondary iron overload due to repeated blood transfusions. Our results may help characterize the pathophysiologic features of cardiomyopathy in patients with secondary iron overload, and our model may be applied to in vivo iron-chelating therapy studies.

Polymorphisms of human leukocyte antigen genes in korean children with Kawasaki disease.

BACKGROUND: Kawasaki disease is a leading cause of acquired heart disease in children. The prevalence rate varies in different ethnic groups. Recently, with the clinical application of molecular genetic technology, human leukocyte antigen (HLA) polymorphisms associated with several diseases have been identified by DNA analysis. This study aimed to assess the association of HLA alleles with susceptibility and complications of Kawasaki disease in Korean children. METHODS: In this study, DNA was extracted from 74 children with a diagnosis of Kawasaki disease. The polymorphisms of the HLA-A, -B, -C, and -DRB1 alleles of patients with Kawasaki disease were determined by polymerase chain reaction (PCR)-amplification refractory mutation system (ARMS) and PCR-sequence-specific primer (SSP) analysis. The polymorphisms identified were compared with those of 159 normal healthy control subjects. RESULTS: There was a significant increase in the frequencies of the HLA-B35, -B75, and -Cw09 alleles in patients with Kawasaki disease compared with the healthy control group. There was no increase in the frequency of HLA-DRB1 alleles among the Kawasaki disease patients compared with a healthy control group. When the patients with Kawasaki disease were divided into two subgroups, with or without coronary complications, the Kawasaki disease patients with coronary complications showed a significantly increased frequency of the HLA-DRB1*11 allele compared with the healthy control group and increased frequency of HLA-DRB1*09 in a comparison of the subgroups. CONCLUSIONS: This study suggests that polymorphisms in some alleles of B and C in HLA class I genes are associated with Kawasaki disease in Korean children.