It is well known that renal cell carcinoma shows poor responses upon chemotherapy, and a multidrug-resistance has been suggested as one of the possible mechanisms of these resistances to chemotherapeutics of renal cell carcinoma as well as other malignancies. We tried to measure the expressions of the multidrug resistance gene and p-glycoprotein in human renal cell carcinoma cell lines, and to evaluate whether various multidrug resistance modulators could enhance the cytotoxicity of adriamycin. Four human renal cell carcinoma cell lines, A-498, A-704, Caki-1, Caki -2, were used and verapamil, cyclosporin A, cefoperazone, quinidine were used as the multidrug resistance modulating agents. Polymerase chain reaction was used to detect the expression of MDR1 mRNA, and measurement of p-glycoprotein was done by FACScan using JSB-1 monoclonal antibody. Cytotoxicity of adriamycin was measured by MTT colorimetric assay. Expression of MDR1 mRNA was observed in A-704, and A-498, but was not detected in Caki-1 and Caki-2. Expression of p-glycoprotein was found in A-498 and A-704, but not in Caki-1 and Caki-2. The relative expression rates of MDR1 and p-glycoprotein in A-498, A-704, Caki-1 and Caki-2 comparing to KB-3-1, the negative control cell line were 1.75, 2.44, 0.98, 0.97 and 1.31, 1.12, 1.08, 0.78 respectively. From these observations, A-498 was selected as MDR positive cell line and Caki-2 as MDR negative cell line, and then a study was performed to evaluate the effect of multidrug resistance modulators on the cytotoxicity of adriamycin upon these cell lines. Verapamil, in concentration of 0.1/microM, did not enhance the anticancer effect of adriamycin on A -498 cells, but with the concentration of 1 microM and 10microM, it decreased IC(50) of adriamycin from 0.43 microgram/ml when only adriamycin was used to 0.21 and 0.16, showing the dose modification effect of 2. 05 and 2.68 respectively (p<0.05, by Mann Whitney test). Cyclosporin A, in all the concentration of 0.3, 1, 3 microM, also decreased IC(50) of adriamycin on A-498 cells to 0.17, 0.14, 0.15 microgram/ml respectively, showing the dose modification effect of 2.53 to 3.07 (p<0.05, by Mann Whitney test). But the cytotoxicity of adriamycin was not influenced by cefoperazone and quinidine. In Caki-2 cells, in which MDR1 and p-glycoprotein expression were barely detected, verapamil and cyclosporin A as well as cefoperazone and quinidine did not show any effect upon the cytotoxicity of adriamycin. Considering above results, verapamil and cyclosporin A seem to be an effective multidrug resistance modulating agents to enhance the cytotoxicity of adriamycin in renal cell carcinoma showing MDR1 and p-glycoprotein expression, and further studies including in vivo study are needed before clinical trials to improve chemotherapeutic effect upon renal cell carcinoma.
Carcinoma, Renal Cell* ; Cefoperazone ; Cell Line* ; Cyclosporine ; Doxorubicin* ; Drug Resistance, Multiple* ; Drug Therapy ; Genes, MDR ; Humans* ; P-Glycoprotein ; Polymerase Chain Reaction ; Quinidine ; RNA, Messenger ; Verapamil

Purpose: Mucin 1 (MUC1) was identified as a gastric cancer (GC) susceptibility gene by genome-wide association studies in Asians and candidate gene studies in Europeans. This study aimed to investigate the association between the MUC1 rs4072037 polymorphism and GC in terms of the Lauren classification and long-term clinical outcomes. Materials and Methods: A total of 803 patients with GC and 816 unrelated healthy controls were enrolled in the study. The association between the MUC1 rs4072037 variant and GC histological types and clinical outcomes, including tumor recurrence and prognosis was investigated. Results: The major A allele of rs4072037 was associated with increased GC risk (P<0.05). In subtype analysis, the association was most significant for diffuse-type GC (P<0.05) and in a dominant model (P<0.05), whereas there was no association with intestinal-type GC (P>0.05). Cox proportional hazards analysis revealed the heterozygote AG rs4072037 allele as an independent risk factor influencing tumor recurrence and disease-related death in diffuse-type GC (P<0.05). but not in intestinal-type GC (P>0.05). Conclusions The exonic single nucleotide polymorphism rs4072037 in MUC1 was associated with diffuse-type GC and was an independent risk factor influencing tumor recurrence and disease-related death in diffuse-type GC.

BACKGROUND/AIMS: Toll-like receptors (TLRs) serve as pattern recognition receptors that recognize specific molecular patterns of pathogens and can mediate the production of proinflammatory cytokines. Recently, TLRs have been identified as susceptibility genes for Crohn's disease (CD) in several studies from Western populations. We investigated the association of genetic variations in TLR4 and TLR9 with CD in Korean population. METHODS: In 380 CD cases and 380 healthy controls, we performed genotyping for TLR4 Asp299Gly (rs4986790) and Thr399Ile (rs4986791). The genetic variations in the TLR9 -1237T/C (rs5743836) were also examined. RESULTS: Among CD patients genotyped for TLR4 Asp299Gly and TLR9 -1237T/C, none had variant alleles. Similarly, none of the subjects genotyped for TLR4 Thr399Ile showed genetic variations. CONCLUSIONS: Our results indicate that the major genetic variations in TLR4 and TLR9 are rare and may not be associated with susceptibility to CD in Koreans.
Adolescent ; Adult ; Alleles ; Asian Continental Ancestry Group/*genetics ; Crohn Disease/diagnosis/ethnology/*genetics ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Republic of Korea ; Toll-Like Receptor 4/*genetics ; Toll-Like Receptor 9/*genetics

Dilated cardiomyopathy (DCM) is characterized by cardiac dilation and systolic dysfunction. So far sixteen genes have been shown to cause autosomal dominant familial dilated cardiomyopathy (FDC). We identified a large Korean family from the Jeju island showing a clear Mendelian inheritance of FDC. A genomewide linkage scan at 9 cM marker density identified a peak multipoint LOD score of 2.82 at D1S195. Haplotyping of the region with 15 additional markers defined a candidate interval that included a known candidate gene encoding the lamin A/C (LMNA). Sequencing of the LMNA exons revealed one missense mutation at C568T (Arg190Trp) in the alpha-helical rod domain of the LMNA gene cosegregating with FDC with conduction-system disease. The same mutation was found in patients of another Korean family with FDC without conduction-system disease. Upon screening 14 sporadic DCM cases, we found three LMNA mutations including a case having a previously described (Glu161Lys) mutation and two having novel mutations (Glu53Val and Glu186Lys). Our results suggest that variable genotypes of laminopathy are implicated in not only familial but also considerable proportion of sporadic DCM.
Pedigree ; Mutation/genetics ; Molecular Sequence Data ; Male ; Lamins/classification/*genetics ; Korea ; Humans ; Genetic Predisposition to Disease ; Female ; Cardiomyopathy, Dilated/*genetics/*pathology ; Base Sequence ; Amino Acid Sequence ; Adult

PURPOSE: High mobility group box 1 (HMGB1) plays a central role in the pathogenesis of sepsis and multiple organ dysfunction syndromes. We investigated the associations of a single nucleotide polymorphism (SNP; rs1045411) in HMGB1 with various clinical parameters, severity, and prognosis in patients with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: We enrolled 212 adult patients followed for 28 days. All patients were genotyped for rs1045411, and the serum levels of HMGB1 and several cytokines were measured. RESULTS: The proportions of patients according to genotype were GG (71.2%), GA (26.4%), and AA (2.4%). Among patients with chronic lung disease comorbidity, patients with a variant A allele had higher positive blood culture rates and higher levels of various cytokines [interleukin (IL)-1beta, IL-6, IL-10, IL-17, and tumor necrosis factor-alpha] than those with the GG genotype. In the analysis of those with diabetes as a comorbidity, patients with a variant A allele had higher blood culture and Gram-negative culture rates than those with GG genotypes; these patients also had a higher levels of IL-17. In the analysis of those with sepsis caused by a respiratory tract infection, patients with a variant A allele had higher levels of IL-10 and IL-17 (all p<0.05). This polymorphism had no significant impact on patient survival. CONCLUSION: The variant A allele of rs1045411 appears to be associated with a more severe inflammatory response than the GG genotype under specific conditions.
Adult ; Aged ; Alleles ; Asian Continental Ancestry Group/genetics ; China/epidemiology ; Cytokines/*blood/*genetics ; Female ; Genotype ; HMGB1 Protein/blood/*genetics ; Humans ; Interleukin-10/genetics ; Interleukin-17/genetics ; Interleukin-6/blood ; Male ; Middle Aged ; Polymorphism, Genetic/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Prognosis ; Republic of Korea ; Sepsis/immunology/*metabolism/mortality ; Shock, Septic/immunology/*metabolism/mortality ; Survival ; Tumor Necrosis Factor-alpha/genetics

BACKGROUND: Mannose-binding lectin (MBL) deficiency leads to increased susceptibility to infection. We investigated whether serial changes in MBL levels are associated with the prognosis of patients diagnosed with septic shock, and correlated with cytokine levels. METHODS: We enrolled 131 patients with septic shock in the study. We analyzed the serum samples for MBL and cytokine levels at baseline and 7 days later. Samples on day 7 were available in 73 patients. RESULTS: We divided the patients with septic shock into four groups according to serum MBL levels ( < 1.3 µg/mL or ≥1.3 µg/mL) on days 1 and 7. Patients with low MBL levels on day 1 and high MBL levels on day 7 showed a favorable prognosis for 28-day survival (odds ratio, 1.96, 95% confidence interval, 1.10–2.87; p=0.087). The high MBL group on day 7 showed a significant decrease in monocyte chemoattractant protein 1, interleukin (IL)-1β, IL-6, IL-8, interferon-γ, and granulocyte macrophage colony-stimulating factor levels compared with the low MBL group on day 7. CONCLUSION: The increase in MBL levels of patients with septic shock may suggest a favorable prognosis and attenuate pro-inflammatory and anti-inflammatory responses.
Chemokine CCL2 ; Cytokines ; Granulocytes ; Humans ; Interleukin-6 ; Interleukin-8 ; Interleukins ; Macrophage Colony-Stimulating Factor ; Mannose-Binding Lectin* ; Prognosis ; Sepsis* ; Shock, Septic

BACKGROUND/AIMS: The aim of this study was to identify the profile of rare variants associated with Crohn's disease (CD) using whole exome sequencing (WES) analysis of Korean children with CD and to evaluate whether genetic profiles could provide information during medical decision making. METHODS: DNA samples from 18 control individuals and 22 patients with infantile, very-early and early onset CD of severe phenotype were used for WES. Genes were filtered using panels of inflammatory bowel disease (IBD)-associated genes and genes of primary immunodeficiency (PID) and monogenic IBD. RESULTS: Eighty-one IBD-associated variants and 35 variants in PID genes were revealed by WES. The most frequently occurring variants were carried by nine (41%) and four (18.2%) CD probands and were ATG16L2 (rs11235604) and IL17REL (rs142430606), respectively. Twenty-four IBD-associated variants and 10 PID variants were predicted to be deleterious and were identified in the heterozygous state. However, their functions were unknown with the exception of a novel p.Q111X variant in XIAP (X chromosome) of a male proband. CONCLUSIONS: The presence of many rare variants of unknown significance limits the clinical applicability of WES for individual CD patients. However, WES in children may be beneficial for distinguishing CD secondary to PID.
Asian Continental Ancestry Group/genetics ; Carrier Proteins/genetics ; Child ; Child, Preschool ; Crohn Disease/*genetics ; *Exome ; Female ; Genetic Predisposition to Disease ; *Genetic Variation ; Humans ; Immunologic Deficiency Syndromes/genetics ; Infant ; Male ; Phenotype ; Receptors, Interleukin-17/genetics ; Republic of Korea ; Sequence Analysis, DNA/*methods ; X-Linked Inhibitor of Apoptosis Protein/genetics

Single nucleotide polymorphisms (SNPs) are the most abundant forms of human genetic variations and resources for mapping complex genetic traits and disease association studies. We have constructed a linkage disequilibrium(LD) map of chromosome 22 in Korean samples and compared it with those of other populations, including Yorubans in Ibadan, Nigeria (YRI), Centred'Etude du Polymorphisme Humain (CEPH) reference families (CEU), Japanese in Tokyo (JPT) and Han Chinese in Beijing (CHB) in the HapMap database. We genotyped 4681 of 111,448 publicly available SNPs in 90 unrelated Koreans. Among genotyped SNPs, 4167 were polymorphic. Three hundred and five LD blocks were constructed to make up 18.6% (6.4 of 34.5 Mb) of chromosome 22 with 757 tagSNPs and 815 haplotypes(frequency > or = 5.0%). Of 3430 common SNPs genotyped in all five populations, 514 were monomorphic in Koreans. The CHB + JPT samples have more than a 72% overlap with the monomorphic SNPs in Koreans, while the CEU + YRI samples have less than a 38% overlap. The patterns of hot spots and LD blocks were dispersed throughout chromosome 22, with some common blocks among populations, highly concordant between the three Asian samples. Analysis of the distribution of chimpanzee-derived allele frequency (DAF), a measure of genetic differentiation, Fst levels, and allele frequency difference (AFD) among Koreans and the HapMap samples showed a strong correlation between the Asians, while the CEU and YRI samples showed a very weak correlation with Korean samples. Relative distance as a quantitative measurement based upon DAF, Fst, and AFD indicated that all three Asian samples are very proximate, while CEU and YRI are significantly remote from the Asian samples. Comparative genome-wide LD studies provide useful information on the association studies of complex diseases.
Asian Continental Ancestry Group ; Chromosomes, Human, Pair 22 ; Gene Frequency ; Genetic Variation ; Haplotypes ; HapMap Project ; Humans ; Nigeria ; Polymorphism, Single Nucleotide ; Tokyo

Single nucleotide polymorphisms (SNPs) are the most abundant forms of human genetic variations and resources for mapping complex genetic traits and disease association studies. We have constructed a linkage disequilibrium(LD) map of chromosome 22 in Korean samples and compared it with those of other populations, including Yorubans in Ibadan, Nigeria (YRI), Centred'Etude du Polymorphisme Humain (CEPH) reference families (CEU), Japanese in Tokyo (JPT) and Han Chinese in Beijing (CHB) in the HapMap database. We genotyped 4681 of 111,448 publicly available SNPs in 90 unrelated Koreans. Among genotyped SNPs, 4167 were polymorphic. Three hundred and five LD blocks were constructed to make up 18.6% (6.4 of 34.5 Mb) of chromosome 22 with 757 tagSNPs and 815 haplotypes(frequency > or = 5.0%). Of 3430 common SNPs genotyped in all five populations, 514 were monomorphic in Koreans. The CHB + JPT samples have more than a 72% overlap with the monomorphic SNPs in Koreans, while the CEU + YRI samples have less than a 38% overlap. The patterns of hot spots and LD blocks were dispersed throughout chromosome 22, with some common blocks among populations, highly concordant between the three Asian samples. Analysis of the distribution of chimpanzee-derived allele frequency (DAF), a measure of genetic differentiation, Fst levels, and allele frequency difference (AFD) among Koreans and the HapMap samples showed a strong correlation between the Asians, while the CEU and YRI samples showed a very weak correlation with Korean samples. Relative distance as a quantitative measurement based upon DAF, Fst, and AFD indicated that all three Asian samples are very proximate, while CEU and YRI are significantly remote from the Asian samples. Comparative genome-wide LD studies provide useful information on the association studies of complex diseases.
Asian Continental Ancestry Group ; Chromosomes, Human, Pair 22 ; Gene Frequency ; Genetic Variation ; Haplotypes ; HapMap Project ; Humans ; Nigeria ; Polymorphism, Single Nucleotide ; Tokyo

Background/Aims: Chronic enteropathy associated with SLCO2A1 gene (CEAS), an inherited disease characterized by nonspecific intestinal ulcers, has emerged in the Japanese population via loss-of-function mutations in the SLCO2A1 gene. We aimed to investigate the clinical and genetic characteristics of Korean patients diagnosed with CEAS. Methods: From July 2018 to July 2021, we performed Sanger sequencing of the SLCO2A1 gene in 46 patients with chronic intestinal ulcers. CEAS was confirmed based on known SLCO2A1 mutations. We summarized the clinical characteristics of patients with confirmed CEAS. Results: Fourteen out of 46 patients (30.4%) had genetically confirmed CEAS, and two SLCO2A1variants were detected (splicing site variant c.940+1G>A and nonsense mutation [p.R603X] in SLCO2A1). Twelve patients (85.7%) were females and the median age at diagnosis of CEAS was 44.5 years. All patients presented with abdominal pain, and 13 patients (92.9%) presented with anemia (median hemoglobin, 9.6 g/dL). Ten patients (71.4%) had hypoalbuminemia (median, 2.7 g/dL). The most commonly involved site was the ileum (13/14, 92.9%). Manifestations of primary hypertrophic osteoarthropathy (PHO), such as digital clubbing, pachydermia, and periostosis were observed in five patients (28.6%) and two male patients and one female patient satisfied all major PHO diagnostic criteria. Conclusions The clinical and genetic characteristics of Korean patients with confirmed CEAS were similar to those reported in the literature. CEAS should be considered in the differential diagnosis for patients with unexplained chronic nonspecific ulcers of the small intestine.