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ABSTRACT: OBJECTIVE: Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP-positive or-negative RA. METHODS: All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression. RESULTS: SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE-positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46-0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA-DRB1*04:05/*09:01. CONCLUSION: HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/*09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently.
The Journal of Rheumatology 05/2013; · 3.69 Impact Factor
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ABSTRACT: Antituberculosis drug (ATD)-induced hypersensitivity syndrome (HSS) is a serious adverse reaction to ATDs, but much remains to be determined regarding its characteristics and genetic risk factors. In this study, we have collected cases of ATD-induced HSS and their clinical features, and investigated the associations of ATD-induced HSS with human leukocyte antigen (HLA). Subjects with ATD-induced HSS and ATD-tolerant controls were recruited through analysis of a multicenter adverse drug reaction registry in Korea. HLA allele frequencies were compared between subjects with ATD-induced HSS (n = 14) and two control groups: ATD-tolerant controls (n = 166) and the general population (n = 485). The number of enrolled subjects with ATD-induced HSS (n = 14) was comparable to those of patients with HSS induced by other common drugs such as allopurinol during the recruitment period. The frequency of Cw*0401 was much higher in the cases (50.0%) compared with ATD-tolerant controls (12.7%, Pc = 0.0204, OR = 6.90) and the general population (12.8%, Pc = 0.0132, OR = 6.82). Our results suggest that ATD is an important causative agent inducing HSS with distinct clinical features. The strong association of Cw*0401 with the risk for ATD-induced HSS suggests immunological involvement in the development of this syndrome.
Tuberculosis (Edinburgh, Scotland) 11/2012; · 2.54 Impact Factor
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Dong Hoon Kang,
Doo Jae Lee, Kyung Wha Lee,
Yoon Sun Park,
Joo Young Lee,
Sang-Hee Lee,
Young Jun Koh,
Gou-Young Koh,
Chulhee Choi,
Dae-Yeul Yu,
Jaesang Kim,
Sang Won Kang
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ABSTRACT: Cellular antioxidant enzymes play crucial roles in aerobic organisms by eliminating detrimental oxidants and maintaining the intracellular redox homeostasis. Therefore, the function of antioxidant enzymes is inextricably linked to the redox-dependent activities of multiple proteins and signaling pathways. Here, we report that the VEGFR2 RTK has an oxidation-sensitive cysteine residue whose reduced state is preserved specifically by peroxiredoxin II (PrxII) in vascular endothelial cells. In the absence of PrxII, the cellular H(2)O(2) level is markedly increased and the VEGFR2 becomes inactive, no longer responding to VEGF stimulation. Such VEGFR2 inactivation is due to the formation of intramolecular disulfide linkage between Cys1199 and Cys1206 in the C-terminal tail. Interestingly, the PrxII-mediated VEGFR2 protection is achieved by association of two proteins in the caveolae. Furthermore, PrxII deficiency suppresses tumor angiogenesis in vivo. This study thus demonstrates a physiological function of PrxII as the residential antioxidant safeguard specific to the redox-sensitive VEGFR2.
Molecular cell 11/2011; 44(4):545-58. · 14.61 Impact Factor
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Sae-Hoon Kim, Kyung Wha Lee,
Woo-Jung Song,
Sang-Heon Kim,
Young-Koo Jee,
Sang-Min Lee,
Hye-Ryun Kang,
Heung-Woo Park,
Sang-Heon Cho,
Seong-Ho Park,
Kyung-Up Min,
Yoon-Seok Chang
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ABSTRACT: Although the US FDA recommends screening for HLA-B*1502 allele in most of Asian ancestry before initiating carbamazepine therapy, the HLA associations with carbamazepine hypersensitivity in non-Chinese Asian populations remain unclear. This study investigated the association between the HLA class I genotype and carbamazepine-induced severe cutaneous adverse reaction (SCAR) in Koreans.
Twenty-four patients who had developed carbamazepine-induced SCAR (7 Stevens-Johnson syndrome (SJS), 17 drug hypersensitivity syndrome (HSS)), 50 carbamazepine-tolerant controls from the Korean Pharmacogenetic Adverse Drug Reaction Research Network and data of 485 Korean general population from a previously published study were recruited. HLA-A, -B, and -C genotyping was performed by direct DNA sequence analysis.
Only one of the seven SJS patients was positive for the B*1502 allele, but the frequency of B*1511 was much higher in the patients with CBZ-SJS than in the CBZ-tolerant control patients (P=0.011, P(c)=not significant; OR=18.0(2.3-141.2)). The frequencies of A*3101 in carbamazepine-induced HSS and SCAR were significantly higher than those in carbamazepine-tolerant controls (P(c)=0.011, OR=8.8(2.5-30.7) and P(c)=0.013, OR=7.3(2.3-22.5), respectively). The frequencies of B*1511 in carbamazepine-SJS and A*3101 in carbamazepine-HSS/SCAR were significantly higher than those in the general population.
HLA-B*1502 does not seem to be an effective predictive marker for carbamazepine-induced SCAR, while HLA-B*1511 and A*3101 was associated with carbamazepine-induced SJS and HSS/SCAR respectively in the Korean population.
Epilepsy research 09/2011; 97(1-2):190-7. · 2.48 Impact Factor
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ABSTRACT: Alleles of the C*07:01/07:06/07:18 group is distinguished by polymorphisms in exons 5-6. In a previous study, we focused on exons 2-3 of the gene and showed that 6.8% of Koreans express alleles in this group. In this study, we identified allelic and haplotypic diversities of the C*07:01/07:06/07:18 group in Koreans. Among 118 C*07:01/07:06/07:18-positive, unrelated, healthy samples, 96.6% were C*07:06 and 3.4% were C*07:01. Each allele was exclusively associated with a specific set of other alleles consisting of the conserved haplotypes A*01:01-C*07:01-B*08:01-DRB1*03:01-DQB1*02:01 (100%) and A*33:03-C*07:06-B*44:03-DRB1*07:01-DQB1*02:02 (95.6%), respectively. None carried C*07:18. With the continuous discovery of novel alleles, periodic updates with testing for newer alleles will be useful to support related research and clinical settings in each population.
Human immunology 05/2011; 72(9):723-6. · 2.55 Impact Factor
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Jae-Woo Jung,
Woo-Jung Song,
Yon-Su Kim,
Kwon Wook Joo, Kyung Wha Lee,
Sae-Hoon Kim,
Heung-Woo Park,
Yoon-Seok Chang,
Sang-Heon Cho,
Kyung-Up Min,
Hye-Ryun Kang
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ABSTRACT: Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B*5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B*5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population. Objective. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity.
We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010.
Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens-Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (-)]. Among patients without HLA-B58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol.
In this study, the incidence of allopurinol-induced SCARs was considerably high in CRI patients with HLA-B58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.
Nephrology Dialysis Transplantation 03/2011; 26(11):3567-72. · 3.40 Impact Factor
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Hye-Ryun Kang,
Young Koo Jee,
Yon-Soo Kim,
Chang Hwa Lee,
Jae-Woo Jung,
Sae Hoon Kim,
Heung-Woo Park,
Yoon-Seok Chang,
In-Jin Jang,
Sang-Heon Cho,
Kyung-Up Min,
Sang-Heon Kim, Kyung Wha Lee
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ABSTRACT: Recent investigations suggest genetic susceptibility of allopurinol-induced severe cutaneous adverse reactions (SCARs). However, the strength of association was variable according to phenotypes and ethnic backgrounds. To explore genetic markers for allopurinol-induced SCARs in Koreans, we genotyped human leukocyte antigen (HLA) class I alleles of 25 cases of allopurinol-induced SCARs (20 cases of drug-induced hypersensitivity syndrome and five cases of Stevens-Johnson syndrome/toxic epidermal necrolysis) and 57 patients tolerant to allopurinol. Frequencies of B*5801 [92.0 vs. 10.5%, P(c)=2.45×10(-11), odds ratio (OR)=97.8], Cw*0302 (92.0 vs. 12.3%, P(c)=9.39×10(-11), OR=82.1), and A*3303 (88.0 vs. 26.3%, P(c)=3.31×10(-6), OR=20.5) were significantly higher in SCARs compared with tolerant controls. In contrast, A*0201 was not found in SCARs patients despite relatively high frequency in tolerant controls (29.8%). We found strong positive association of HLA-B*5801 and negative association of HLA-A*0201 with the development of allopurinol-induced SCARs in the Korean population.
Pharmacogenetics and Genomics 02/2011; 21(5):303-7. · 3.48 Impact Factor
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ABSTRACT: The 2-Cys peroxiredoxins (Prx) belong to a family of antioxidant enzymes that detoxify reactive oxygen and nitrogen species and are distributed throughout the intracellular and extracellular compartments. However, the presence and role of 2-Cys Prxs in the nucleus have not been studied. This study demonstrates that the PrxII located in the nucleus protects cancer cells from DNA damage-induced cell death. Although the two cytosolic 2-Cys Prxs, PrxI and PrxII, were found in the nucleus, only PrxII knockdown selectively and markedly increased cell death in the cancer cells treated with DNA-damaging agents. The increased death was completely reverted by the nuclearly targeted expression of PrxII in an activity-independent manner. Furthermore, the antioxidant butylated hydroxyanisole did not influence the etoposide-induced cell death. Mechanistically, the knockdown of Prx II expression impaired the DNA repair process by reducing the activation of the JNK/c-Jun pathway. These results suggest that PrxII is likely to be attributed to a tumor survival factor positively regulating JNK-dependent DNA repair with its inhibition possibly sensitizing cancer cells to chemotherapeutic agents.
Journal of Biological Chemistry 12/2010; 286(10):8394-404. · 4.77 Impact Factor
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ABSTRACT: Human leukocyte antigen (HLA) gene region encodes a set of HLA molecules functioning critical roles in immune response. Each HLA gene locus shows extensive polymorphism with ever-increasing number of alleles. The HLA nomenclature system for alleles defined by DNA typing was first established in 1987 and has been revised several times. Recently, it has been revised again with a new frame that can accommodate ever-increasing number of new alleles. The new system has also introduced the novel suffixes, P and G, to simplify reporting of ambiguous strings of alleles in typing reports. This review introduces the HLA nomenclature system-2010 in conjunction with its clinical application in Koreans.
The Korean Journal of Laboratory Medicine 06/2010; 30(3):203-17. · 0.63 Impact Factor
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ABSTRACT: The carbonic anhydrase inhibitor methazolamide infrequently causes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). An association between these diseases and the HLA-B59 serotype has been suggested in case reports. This study examined the disease-associated B*59 allele and investigated the association of these diseases with other HLA class I alleles.
We performed high-resolution HLA-A, -B and -C genotyping in five patients with methazolamide-induced SJS/TEN using a PCR-sequencing-based typing method and analyzed the association between HLA-class I alleles and occurrence of methazolamide-induced SJS/TEN.
B*5901 and Cw*0102 alleles were observed in all patients and A*2402 was observed in four patients. The B*5901 allele showed the strongest association with methazolamide-induced SJS/TEN (p < 0.001; odds ratio: 249.8; 95% CI: 13.4-4813.5), followed by Cw*0102 (p = 0.004; odds ratio: 22.1; 95% CI: 1.2-414.3), when compared with the general population as a control. The frequency of the patients carrying B*5901, Cw*0102 and A*2402 simultaneously was significantly higher than that in the general population (p < 0.001; odds ratio: 110.1; 95% CI: 11.7-1038.6).
A strong association was observed between HLA-B*5901 and methazolamide-induced SJS/TEN in Korean patients. HLA-B*5901 may be a useful screening marker for predicting methazolamide-induced SJS/TEN in patients of Korean and Japanese ancestry.
Pharmacogenomics 06/2010; 11(6):879-84. · 3.97 Impact Factor
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ABSTRACT: Smoking is associated with rheumatoid arthritis (RA) in individuals with the HLA-DRB1 shared epitope (SE). SE alleles have been shown to be predominantly associated with anti-cyclic citrullinated peptide (anti-CCP)-positive RA. These risk factors have not been identified for anti-CCP-negative RA. The aim of this study was to investigate whether SE-containing HLA-DRB1 alleles, smoking, or the combination of these factors contributes to the development of RA, depending on the presence or absence of serologic markers, in a Korean population.
All of the patients with RA (n =1,482) and all of the control subjects (n = 1,119) were Korean. Four-digit HLA-DRB1 typing was performed by a conventional polymerase chain reaction-sequence-based typing method. Information about smoking history was obtained through a questionnaire. The patients with RA were tested for anti-CCP antibodies and rheumatoid factor (RF).
The SE alleles had significant effects on anti-CCP antibody and RF formation. The DRB1*0901 allele was associated with the presence of anti-CCP antibodies (odds ratio [OR] 2.49) and RF (OR 2.09). SE alleles and smoking were associated with both anti-CCP-positive and anti-CCP-negative RA. The combination of smoking and double copies of the SE allele increased the risk of anti-CCP-positive RA 36.11-fold and increased the risk of anti-CCP-negative RA 12.29-fold, compared with the risk among nonsmokers not carrying SE alleles. Interactions between SE alleles and smoking were observed for both anti-CCP-positive and RF-positive RA, although the associations of RF-positive RA could be consequences of the underlying anti-CCP antibody status.
We demonstrated that the combination of SE alleles and smoking is associated with RA susceptibility regardless of anti-CCP antibody or RF status, but that the combination shows stronger effects in anti-CCP-positive/RF-positive patients with RA than in anti-CCP-negative/RF-negative patients with RA. The SE-smoking interactions were present in anti-CCP-positive and RF-positive RA.
Arthritis & Rheumatism 02/2010; 62(2):369-77. · 7.87 Impact Factor
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Jung Nyeo Chun,
Boae Choi, Kyung Wha Lee,
Doo Jae Lee,
Dong Hoon Kang,
Joo Young Lee,
In Sung Song,
Hye In Kim,
Sang-Hee Lee,
Hyeon Soo Kim,
Na Kyung Lee,
Soo Young Lee,
Kong-Joo Lee,
Jaesang Kim,
Sang Won Kang
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ABSTRACT: Cytoplasmic presence of Hsp60, which is principally a nuclear gene-encoded mitochondrial chaperonin, has frequently been stated, but its role in intracellular signaling is largely unknown. In this study, we demonstrate that the cytosolic Hsp60 promotes the TNF-alpha-mediated activation of the IKK/NF-kappaB survival pathway via direct interaction with IKKalpha/beta in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-kappaB activation and the expression of NF-kappaB target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-alpha. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-kappaB activation. Mechanistically, the cytosolic Hsp60 enhanced IKK activation via upregulating the activation-dependent serine phosphorylation in a chaperone-independent manner. Furthermore, transgenic mouse study showed that the cytosolic Hsp60 suppressed hepatic cell death induced by diethylnitrosamine in vivo. The cytosolic Hsp60 is likely to be a regulatory component of IKK complex and it implicates the first mitochondrial factor that regulates cell survival via NF-kappaB pathway.
PLoS ONE 01/2010; 5(3):e9422. · 4.09 Impact Factor
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ABSTRACT: Gastric carcinogenesis is a multi-step process and is influenced by several etiological agents, including the host's genetic factors. Since whether a patient remains with chronic superficial gastritis (CSG) or progresses to either chronic atrophic gastritis (CAG) or gastric carcinoma (GC) could be a genetic predisposition unique in each population, we hypothesized that host human leukocyte antigen (HLA) alleles could be discriminative in predicting the risk of CSG progression to precancerous CAG and GC in Koreans.
A total of 165 patients with gastric disorders (CSG, 62; CAG, 69 and GC, 34), were selected to investigate the association of HLA class II alleles with the progression of CSG to CAG or GC. HLA genotypes were obtained by the polymerase chain reaction-sequence based typing method.
The phenotypic frequencies of DRB1*1101 and DQA1*0505 were significantly higher in the CAG group compared to those in the CSG group. In the subjects with Helicobacter pylori (H. pypori) (+), the frequencies of DRB1*1501 and DQB1*0602 were significantly lower in the CAG compared to those in the CSG. Further analysis showed that sex (P < 0.05, OR = 0.41-0.42) and age (P < 0.05, OR = 1.05) also affected the risk of progression from CSG to CAG in H. pylori (+) patients carrying the DRB1*1501 or DQB1*0602 allele. Additionally, the frequency of DRB1*0404 in the GC group was significantly higher than that in the gastritis group.
Our findings strongly imply an association between HLA class II alleles and the risk of CAG development and GC progression in Koreans.
Journal of Digestive Diseases 11/2009; 10(4):265-71. · 1.59 Impact Factor
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Jeong-Hee Choi, Kyung Wha Lee,
Hye-Ryun Kang,
Yong Il Hwang,
SeungHun Jang,
Dong-Gyu Kim,
Cheol-Hong Kim,
In-Gyu Hyun,
Tae-Rim Shin,
Sang-Myeon Park,
Myung-Goo Lee,
Chang-Youl Lee,
Yong-Bum Park,
Ki-Suck Jung
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ABSTRACT: Early detection of drug-resistant Mycobacterium tuberculosis is important for the control and prevention of disease transmission. However, conventional drug susceptibility tests for drug-resistant M tuberculosis take at least 3 to 8 weeks. Here, we report the clinical efficacy of direct DNA sequencing analysis for detecting drug-resistant TB on sputum specimens in a clinical setting.
A total of 113 sputum specimens from 111 patients, who were suspected of having drug-resistant TB by clinicians, were used for DNA sequencing of katG, rpoB, embB, and pncA genes for isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) resistance, respectively, and the results were compared with drug susceptibility tests. The optimization of antituberculosis drugs according to the results of DNA sequencing and the treatment outcomes of the patients were also analyzed.
Turnaround time of the direct DNA sequencing analysis was 3.8 +/- 1.8 days. We found mutations related to drug resistance in 30 clinical specimens for katG, 39 for rpoB, 13 for embB, and 24 for pncA. The sensitivity and specificity of the assay were 63.6% and 94.6% for INH, 96.2 and 93.9% for RIF, 69.2% and 97.5% for EMB, and 100% and 92.6% for PZA, respectively. Of the patients with RIF resistance, including multidrug-resistant TB by the assay, 92.5% of the patients with initial first-line antituberculosis drugs were changed to second-line antituberculosis drugs, and treatment was successful in 61.9% of these cases.
Direct DNA sequencing analysis of clinical sputum specimens is a rapid and useful method for the detection and treatment of drug-resistant TB.
Chest 10/2009; 137(2):393-400. · 5.25 Impact Factor
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Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 09/2009; 103(2):174-5. · 2.83 Impact Factor
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ABSTRACT: Although the pathogenesis of toluene diisocyanate (TDI)-induced occupational asthma (TDI-OA) is incompletely understood, several studies have suggested immunologic mechanisms, including specific IgE responses. A few studies have suggested human leukocyte antigen (HLA) associations with TDI-induced asthma in Western countries, but this is the first investigation of associations between HLA class I and II alleles and TDI-induced asthma patients in Asia, using high-resolution analysis.
Patients with TDI-OA (n = 84), asymptomatic exposed controls (AECs, n = 47) and unexposed normal controls (NCs, n = 127) were enrolled. HLA class I and II genotyping was performed by the direct DNA sequencing analysis. Specific serum IgE antibodies to the vapor type TDI-albumin conjugate were measured by ELISA.
There was no significant association between the allele frequencies and the phenotype of TDI-OA. However, the frequency of the HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype was significantly higher in TDI-OA patients (19%) than in AEC (2.1%, p = 0.007, OR 4.429, CI 1.497-13.103) or NC (3.1%, p < 0.001, OR 7.235, CI 2.236-22.510) subjects, with statistical significance persisting after correction for multiple comparisons. DQB1*0402 was significantly associated with the presence of specific IgE to TDI-albumin conjugates in serum (p = 0.006, OR 4.552, CI 1.540-13.449). This p value remained significant after correction for multiple comparison.
The HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be a genetic marker for the development of TDI-induced asthma in Koreans. Several HLA alleles that enhance specific IgE sensitization in exposed subjects are indicated.
International Archives of Allergy and Immunology 05/2009; 150(2):156-63. · 2.40 Impact Factor
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ABSTRACT: It has been speculated that human leukocyte antigen (HLA) alleles are associated with the outcome of hepatitis B virus (HBV) infection although the data obtained from various populations have shown some inconsistencies. A total of 464 HBVinfected Korean individuals (80 spontaneously recovered [SR] and 384 chronically infected [CI]) were selected to investigate the association of HLA class II alleles with the viral clearance and persistence. Our results showed that: 1) multiple HLA class II alleles and haplotypes were associated with viral clearance (DRB1*1302, DRB1*1502, DQB1*0302, DQB1*0609, and related-haplotypes) and persistence (DRB1*0701, DQB1*0301, and related-haplotypes); 2) DRB1*1302 and DQB1* 0609 were more strongly associated with viral clearance. And the association of DQB1*0609 (pc=0.0084; OR, 7.24) with vial clearance was much stronger than previously recognized, DRB1*1302 (pc=0.0038; OR, 4.34); and 3) linkage to a specific DPB1 allele in a haplotype strengthened the association with viral clearance, although DPB1 itself was not associated with the outcome. These results indicate the existence of multiple factors controlling viral clearance in the HLA class II gene region. Further extended investigation on the genetic factors related to the outcome of HBV infection will provide valuable insights into the understanding of the mechanisms involved.
Journal of Korean Medical Science 11/2008; 23(5):838-44. · 0.99 Impact Factor
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Seok Goo Cho,
So-Youn Min,
Min Jung Park, Kyung Wha Lee,
Young-Gyu Cho,
Mi-La Cho,
Hong Seok Chang,
Se-Ho Park,
Jong Wook Lee,
Woo Sung Min,
Chun Choo Kim,
Ho-Youn Kim
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ABSTRACT: To investigate the immunoregulatory effects of allogeneic mixed chimerism induced by T cell-depleted, nonmyeloablative bone marrow transplantation (BMT) on chronic inflammatory arthritis and autoimmunity in mice deficient in interleukin-1 receptor antagonist (IL-1Ra).
IL-1Ra(-/-) mice (H-2K(d)) were treated with antibody to asialoganglioside G(M1) (anti-natural killer cell), total body irradiation (500 cGy), and T cell-depleted, nonmyeloablative BMT derived from C57BL/6 mice (H-2K(b)). Engraftment and chimerism were evaluated in peripheral blood, lymph nodes, and spleen by multicolor flow cytometry. The severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Levels of IgG1 and IgG2a subtypes of anti-type II collagen (anti-CII) antibodies were measured in serum samples. After T cells were stimulated with CII, ovalbumin, and phytohemagglutinin, T cell proliferative responses and levels of cytokine production (interferon-gamma [IFNgamma], tumor necrosis factor alpha [TNFalpha], interleukin-10 [IL-10], and IL-17) were assayed in culture supernatants.
All IL-1Ra(-/-) mice receiving BMT showed marked improvement in arthritis within 3 weeks, as well as successful induction of mixed chimerism. These mice showed higher levels of IgG1, and lower levels of IgG2a anti-CII antibodies and weaker T cell proliferative responses than did mice in the control groups (either no treatment or conditioning alone without bone marrow rescue). In mixed chimeras, the levels of IFNgamma, TNFalpha, and IL-17 produced from CII-stimulated T cells were significantly suppressed and IL-10 production was significantly higher as compared with controls.
The introduction of allogeneic mixed chimerism showed a strong immunoregulatory potential to correct established chronic inflammatory arthritis and autoimmunity originating from a dysregulated proinflammatory cytokine network.
Arthritis & Rheumatism 07/2006; 54(6):1878-87. · 7.87 Impact Factor
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Seok Goo Cho,
So-Youn Min,
Min Jung Park, Kyung Wha Lee,
Young-Gyu Cho,
Mi-La Cho,
Hong Seok Chang,
Se-Ho Park,
Jong Wook Lee,
Woo Sung Min,
Chun Choo Kim,
Ho-Youn Kim
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ABSTRACT: Objective
To investigate the immunoregulatory effects of allogeneic mixed chimerism induced by T cell–depleted, nonmyeloablative bone marrow transplantation (BMT) on chronic inflammatory arthritis and autoimmunity in mice deficient in interleukin-1 receptor antagonist (IL-1Ra).MethodsIL-1Ra−/− mice (H-2Kd) were treated with antibody to asialoganglioside GM1 (anti–natural killer cell), total body irradiation (500 cGy), and T cell–depleted, nonmyeloablative BMT derived from C57BL/6 mice (H-2Kb). Engraftment and chimerism were evaluated in peripheral blood, lymph nodes, and spleen by multicolor flow cytometry. The severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Levels of IgG1 and IgG2a subtypes of anti–type II collagen (anti-CII) antibodies were measured in serum samples. After T cells were stimulated with CII, ovalbumin, and phytohemagglutinin, T cell proliferative responses and levels of cytokine production (interferon-γ [IFNγ], tumor necrosis factor α [TNFα], interleukin-10 [IL-10], and IL-17) were assayed in culture supernatants.ResultsAll IL-1Ra−/− mice receiving BMT showed marked improvement in arthritis within 3 weeks, as well as successful induction of mixed chimerism. These mice showed higher levels of IgG1, and lower levels of IgG2a anti-CII antibodies and weaker T cell proliferative responses than did mice in the control groups (either no treatment or conditioning alone without bone marrow rescue). In mixed chimeras, the levels of IFNγ, TNFα, and IL-17 produced from CII-stimulated T cells were significantly suppressed and IL-10 production was significantly higher as compared with controls.Conclusion
The introduction of allogeneic mixed chimerism showed a strong immunoregulatory potential to correct established chronic inflammatory arthritis and autoimmunity originating from a dysregulated proinflammatory cytokine network.
Arthritis & Rheumatism 05/2006; 54(6):1878 - 1887. · 7.87 Impact Factor
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ABSTRACT: To investigate the association of susceptibility and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in an Asian population.
All RA patients (n = 574) and control subjects (n = 392) were Korean. HLA-DRB1 typing and further subtyping of all alleles was performed by polymerase chain reaction, sequence-specific oligonucleotide probe hybridization, and direct DNA sequencing analysis. We used a relative predispositional effects (RPEs) method and a false discovery rate correction method for multiple comparisons.
The DRB1*0405 and *0901 alleles showed the most significant associations with RA (P = 7.83 x 10(-24), odds ratio [OR] 4.40 [95% confidence interval (95% CI) 3.24-5.99], and P = 3.76 x 10(-9), OR 2.47 [95% CI 1.82-3.36], respectively). The RPEs test showed that the DRB1*0401 and *0410 alleles conferred susceptibility and that the DRB1*0701, *0802, *1301, *1302, *1403, and *1405 alleles showed significant protective effects. Susceptibility and protective alleles both showed a pattern consistent with additive genetic effects, and each influenced RA independently of the other. The compound heterozygote DRB1*0405/*0901 was associated with the highest risk of RA (corrected P = 1.81 x 10(-11), OR 58.2 [95% CI 7.95-425.70]). The mean age at disease onset was approximately 4 years earlier or was 3 years earlier, respectively, in patients with at least 1 copy of the DRB1*0405 or the DRB1*0901 allele. Radiographic changes (stages II-IV) were more frequent in patients with at least 1 copy of DRB1*0405 (P = 0.032, 92.6% versus 84.3%, OR 2.33 [95% CI 1.24-4.39]).
The DRB1*0405/*0901 heterozygote has the strongest association with RA, suggesting that this heterozygote enhances the susceptibility to RA in Koreans.
Arthritis & Rheumatism 12/2004; 50(11):3468-75. · 7.87 Impact Factor
