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Objective: To describe the hyperproliferation of Elschnig pearl‐type posterior capsule opacification and concurrent uveitis in two canine eyes after phacoemulsification, followed by spontaneous resolution of the Elschnig pearls. Animal Studied: A 10‐year‐old castrated male Spitz (Case 1) and a 4‐year‐old spayed female Bichon Frise (Case 2). Procedure: Elschnig pearls proliferating beyond the anterior capsulotomy site were observed in the right eye 10 months after bilateral diabetic cataract surgery (Case 1) and 7 months after unilateral cataract surgery (Case 2). In both cases, hyperproliferation occurred where the anterior capsule did not overlap with the intraocular lens (IOL), and was accompanied by aqueous flare. In Case 1, the pearls extended from the anterior capsule and adhered to the iris, causing focal posterior synechia. No other possible causes of uveitis were apparent. Results: Initially, uveitis severity improved after the administration of topical and systemic anti‐inflammatory drugs. However, uveitis recurred when the dosage of anti‐inflammatory treatment was reduced. The Elschnig pearls underwent morphological changes throughout the follow‐up period. In both cases, the pearls beyond the anterior capsulotomy resolved spontaneously after 5 months. Only a few pearls remained between the IOL and posterior capsule, and no recurrence of pearl proliferation was observed at the last follow‐up. Conclusions: To the best of our knowledge, this is the first report of spontaneous Elschnig pearl regression in dogs. Lens‐induced uveitis (LIU) may have been caused by anterior chamber hyperproliferative pearls. LIU associated with hyperproliferative pearls may be managed with appropriate anti‐inflammatory treatment and monitoring. [ABSTRACT FROM AUTHOR]

Objective: Metabolic syndrome is a major health problem worldwide associated with obesity, thus drawing attention to its relation to osteoarthritis (OA). However, it is still uncertain whether metabolic syndrome or body fat distribution is associated with knee OA. The aim of this longitudinal study was to elucidate the association between metabolic obesity and adverse structural changes of knee OA assessed by magnetic resonance imaging (MRI). Methods: Participants were recruited from the Hallym Aging Study cohort in Korea. Knee MRI scans, along with dual‐energy X‐ray absorptiometry, were assessed in 226 participants at baseline and after 3 years. The structural progression in the tibiofemoral joint was evaluated using the semi‐quantitative Whole‐Organ MRI Score (WORMS) for cartilage morphology and bone marrow lesions (BML). Logistic regression with generalized estimating equation was performed for associations of metabolic risk factors with worsening of WORMS scores at the subregional level. Results: In the medial compartment, fat mass in women was associated with cartilage loss, but the statistical significance disappeared after adjusting for body mass index. Metabolic syndrome and each of its components were not associated with cartilage loss or increase of BML. On the other hand, the interaction effects of metabolic syndrome on the association between obesity and knee OA progression were not significant. Conclusion: In this cohort, metabolic effects of obesity on knee cartilage damage and BML were not demonstrated. Further large‐scale studies are required to prove the causal relationship between metabolic obesity and knee OA. [ABSTRACT FROM AUTHOR]

Aim: Peripheral features contribute to disease burden in ankylosing spondylitis (AS). This study investigated the frequency of peripheral disease and effectiveness of adalimumab among Korean patients with AS. Methods: Peripheral disease was evaluated in consecutively enrolled patients with active AS (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] score ≥ 4). An adult subpopulation was subsequently enrolled in a prospective, observational study and received adalimumab 40 mg, every 2 weeks. During a 52‐week follow‐up, AS disease activity was assessed by BASDAI score, and effectiveness in peripheral disease assessed via changes in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES; 0‐13), swollen joint and tender joint counts (SJC, 0‐44; TJC, 0‐46), and dactylitic digits from baseline. Results: Of 1161 Korean patients with AS, 178 (15.3%) and 306 (26.4%) had enthesitis and peripheral arthritis, respectively; dactylitis was diagnosed in 28 patients (2.4%). Of 201 patients enrolled in the observational study, 46.3%, 33.3%, and 3.0% had enthesitis, peripheral arthritis, and dactylitis, respectively. Overall, 75.1% of patients achieved >50% improvement in BASDAI score by week 12. Mean MASES was significantly reduced from 2.67 at baseline to 0.85 and 0.34 at weeks 12 and 52, respectively (P <.0001). Similarly, SJC and TJC improved significantly from 2.58 and 3.49 at baseline to 0.80 and 1.68, respectively, by week 12 (P <.0001). Dactylitis was resolved in all affected patients by week 28. Conclusion: Of these Korean patients with AS, those who received adalimumab demonstrated higher prevalence for peripheral symptoms and, subsequently, adalimumab treatment improved peripheral features of their AS. [ABSTRACT FROM AUTHOR]

To investigate the influence of obesity and obligatory bipedal walking on osteoarthritis (OA) development, 26‐week‐old C57BL/6 mice were divided into two groups and obesity was induced in one group with a 60% fat diet. After 8 weeks, mice from each group were again divided into two groups and obligatory bipedal exercise was induced with a specially designed treadmill in one group, resulting in four experimental groups (control, control bipedal, obese, and obese bipedal). After 8, 10, and 12 weeks of bipedal walking, knee joints were obtained and graded. Surface fibrillation and matrix proteoglycan depletion, began to appear after 8 weeks of exercise in the bipedal groups and progressed as the duration of the exercise increased. At 12 weeks, cartilage loss extending >75% of articular cartilage was observed in none of the control and obese groups, and in 42.8% and 77.7% of control bipedal and obese bipedal animals, respectively. OA grading was significantly higher in the obese bipedal group compared with the control bipedal group. The von Frey fiber test thresholds decreased significantly in the bipedal groups compared with the control and obese groups. This model can be used to study the pathogenesis of human OA and to evaluate its therapeutic agents. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2411–2419, 2019 [ABSTRACT FROM AUTHOR]

This study investigates whether an increase in litigation risk results in Big N auditors leaving the industry and examines the impact of this increase on audit quality. Using a sample of Korean savings banks from 2009 to 2015, the study finds that the proportion of Big N auditors sharply decreases after a savings bank crisis, suggesting that Big N auditors are likely to reject riskier clients, while audit quality is unchanged. The results provide new evidence that an increase in litigation risk does not necessarily increase audit quality. The findings have academic and practical implications, as they suggest that policies for improving audit quality should consider auditors' strategies in response to litigation risk. This study investigates whether an increase in litigation risk results in Big N auditors leaving the industry and examines the impact of this increase on audit quality. Using a sample of Korean savings banks from 2009 to 2015, the study finds that the proportion of Big N auditors sharply decreases after a savings bank crisis, suggesting that Big N auditors are likely to reject riskier clients, while audit quality is unchanged. [ABSTRACT FROM AUTHOR]

Abstract: Aim: We designed this study to evaluate the prevalence of comorbidities, their monitoring states and association with treatment medication in Korean rheumatoid arthritis (RA) patients compared with patients from other countries. Methods: We analyzed 1050 RA patients from 11 Korean centers and compared them with 3520 patients from 16 other countries using an international, cross‐sectional study evaluating comorbidities of RA (COMORA) database. Results: Annual evaluations of cardiovascular (CV) risk were less frequently performed in Korea (P = 0.0011). The prevalence of CV‐associated morbidity was similar between Korean and international RA patients, although the proportions of current smokers, patients with a family history of CV disease, patients with hyperlipidemia, and patients with Framingham score > 20% were significantly lower in Korea (P < 0.0001 for all), and the antiplatelet agents were more optimally used in Korea (P = 0.0004). Prostate cancer screening was less frequently performed compared to other countries (P < 0.0001). Less than 10% of Korean RA patients were given influenza and pneumococcal vaccinations according to current recommendations. Conclusions: There are differences in the prevalence of comorbidities and monitoring states of the risk factors between patients in Korea and in other countries. The prevalence of CV morbidity was similar between the two groups although the prevalence of CV risk factors was significantly low in Korea, suggesting that rheumatologists in Korea need to pay more attention to yearly CV risk monitoring, in addition to the screening of malignancy and vaccination of RA patients against infectious diseases. [ABSTRACT FROM AUTHOR]

We investigate the role of female executives in curbing earnings management behaviour in Korea, a country known for its strong male-dominant culture. In a sample of Korean firms from 2002 to 2010, we find that female presence in top management is negatively associated with discretionary accruals, suggesting that gender diversity in senior management deters opportunistic financial reporting even in a highly male-dominant corporate environment. Further, this association is primarily observed in firms with stronger (weaker) female (male) dominance. This finding is consistent with the idea that female executives can exert more influence on corporate decisions in a more female-friendly environment. These findings have implications for academics and practitioners seeking to understand the impact of the role of top executive gender diversity in corporate accounting practices. [ABSTRACT FROM AUTHOR]

Objective The Disease Activity Score based on 28 joints ( DAS28) has been widely used in clinical practice and research studies of rheumatoid arthritis ( RA). The objective of this study was to evaluate the discordance in the DAS28 based on the erythrocyte sedimentation rate ( ESR) versus C-reactive protein ( CRP) levels in Korean patients with RA. Methods From August to December 2011, 540 patients with RA who visited two rheumatology clinics affiliated with Hallym University (Korea) and had at least one DAS28 evaluation were examined. Results The mean age of the included patients was 53 years, and 82% were female. The mean duration of disease was 32.9 ± 41.2 months. The mean DAS28- ESR was higher than the DAS28- CRP (3.65 vs. 3.44; P < 0.001). In the DAS28- ESR group, 126 patients (23.3%) satisfied the criteria for remission versus 134 (24.8%) in the DAS28- CRP group. High disease activity was determined in 80 (14.8%) patients in the DAS28- ESR group and in 43 (8.0%) in the DAS28- CRP group. A comparison of the two groups with respect to four DAS28 disease activity categories showed agreement in 344 patients (63.7%; κ = 0.45). In classifying patients as European League Against Rheumatism ( EULAR) responders, agreement between the two methods was shown in 56 patients (71.8%; κ = 0.76). When disagreements between the two scores occurred, more patients had a better EULAR response based on the DAS28- ESR than on the DAS28- CRP (19.2% vs. 8.9%, respectively). Conclusion The discordance between the ESR-based and CRP-based DAS28 could affect clinical treatment decisions for patients with RA. [ABSTRACT FROM AUTHOR]

Background: Autonomic dysfunction in idiopathic rapid eye movement sleep behavior disorder patients has not yet been quantified. The aim of this study was to characterize dysautonomia in patients with idiopathic rapid eye movement sleep behavior disorder using the Composite Autonomic Severity Score, which is a validated instrument for the quantitation of autonomic failure.Methods: We prospectively enrolled patients with idiopathic rapid eye movement sleep behavior disorder. A battery of standardized autonomic function tests was performed. Autonomic data obtained from the patients were compared to age- and sex-matched healthy controls.Results: Seventeen patients were enrolled. All but 1 patient showed at least one autonomic deficit. These deficits were predominantly adrenergic and cardiovagal and involved relatively few sudomotor problems. The degree of autonomic dysfunction according to the Composite Autonomic Severity Score was mild to moderate in most patients.Conclusions: Idiopathic rapid eye movement sleep behavior disorder is linked to mild-to-moderate autonomic dysfunction, which is predominantly adrenergic and cardiovagal. [ABSTRACT FROM AUTHOR]

Objective To evaluate the relationships between fat mass, muscle mass, fat:muscle mass ratio, metabolic syndrome, and musculoskeletal pain in community residents. Methods In the Korean Health and Genome Study, 1,530 participants (mean ± SD age 60.8 ± 8.60 years) completed pain questionnaires and underwent dual x-ray absorptiometry to calculate body composition. Pain was categorized according to the number of pain regions, such that widespread pain, defined as pain above the waist, below the waist, on both sides of the body, and in the axial region, represented the most severe pain. Metabolic syndrome was defined using the International Diabetes Federation 2005 recommendations, and the association between metabolic syndrome and pain was evaluated by dividing the population into 4 groups, according to the presence/absence of metabolic syndrome and of high body mass index (BMI). Results Total fat mass and fat:muscle mass ratio were significantly and positively associated with musculoskeletal pain among female subjects only. Compared to the lowest quartile of fat:muscle mass ratio, the odds ratios for widespread pain among subjects in other quartiles were significantly increased after adjustment for confounders. Widespread pain was more prevalent among subjects with metabolic syndrome whether their BMI was high or normal, especially among female subjects. Conclusion Increased fat mass and fat:muscle mass ratio were significantly associated with musculoskeletal pain among women. Widespread pain was significantly associated with a high fat:muscle mass ratio after adjustment for confounders. Understanding the relationship between fat mass and pain may provide insights into preventative measures and therapeutic strategies for musculoskeletal pain. [ABSTRACT FROM AUTHOR]

Objective Although recent imaging studies of fibromyalgia (FM) have converged on a dysfunction of central pain processing as the primary pathophysiologic cause of the disorder, microstructural changes of the white matter (WM) suggestive of abnormalities in the anatomic connectivity of the brain have not been extensively examined. The aim of this study was to investigate WM integrity and its possible relationship to pain symptoms in women with FM. Methods Nineteen FM patients and 21 age-, sex-, and education-matched healthy control subjects were included in the study and underwent diffusion-weighted imaging. Group differences in WM integrity, which were assessed via fractional anisotropy (FA), was investigated by applying tract-based spatial statistics. Results As compared with the healthy control group, the FM group showed a single cluster with lower FA in the left body of the corpus callosum, which was found to be connected to the bilateral sensorimotor cortices ( P < 0.05, corrected for multiple comparisons). Furthermore, FA values in the cluster were negatively associated with sensory pain, as measured by the Short-Form McGill Pain Questionnaire, as well as with the relative magnitude of sensory pain versus affective pain (calculated by dividing the sensory score by the affective score). Conclusion Findings of the current study demonstrated that patients with FM had disrupted WM microstructure in the body of the corpus callosum, which was associated with clinical pain intensity. Our results suggest that abnormal interhemispheric transfer might contribute to the heightened pain perception. Our findings further strengthen the hypothesis of centrally augmented pain processing in patients with FM. [ABSTRACT FROM AUTHOR]

Objective Recent studies have proposed an association between periodontitis and metabolic abnormalities. We investigated the association between insulin resistance and periodontitis among Korean adults. Methods A cross-sectional analysis was conducted using the Korea National Health and Nutrition Examination Survey 2008-2010. A total of 16,720 non-diabetic subjects over 18 years old were evaluated (7060 men and 9660 women). Periodontal status was assessed by the Community Periodontal Index. Insulin resistance was measured using the homeostasis model assessment of insulin resistance ( HOMA- IR). Participants in the highest and lowest quartile of HOMA- IR were defined as insulin-resistant and insulin-sensitive respectively. Results The prevalence of periodontitis increased significantly with higher HOMA- IR quartiles in post-menopausal women ( p for linear association = 0.019). Among post-menopausal women, participants in the highest quartile of HOMA- IR were significantly more likely to have periodontitis compared to those in the lowest quartile [adjusted odds ratio ( OR), 1.47; 95% confidence interval ( CI), 1.07-2.01]. Moreover, obese post-menopausal women showed an increased association between insulin resistance and periodontitis (adjusted OR, 1.92; 95% CI,1.29-2.87). However, this association was not found in men or pre-menopausal women. Conclusions Our results suggest that insulin resistance may be associated with periodontitis, especially when combined with obesity, among post-menopausal women in Korea. [ABSTRACT FROM AUTHOR]

Objective MicroRNAs (miRNAs), small noncoding RNA molecules, are involved in the pathogenesis of various diseases such as cancer and arthritis. The aim of this study was to determine whether miR-127-5p regulates interleukin-1β (IL-1β)-induced expression of matrix metalloproteinase 13 (MMP-13) and other catabolic factors in human chondrocytes. Methods Expression of miR-127-5p and MMP-13 by normal and osteoarthritic (OA) human cartilage was determined using real-time polymerase chain reaction. The effect of miR-127-5p on MMP-13 expression was evaluated using transient transfection of human chondrocytes or chondrogenic SW-1353 cells with miR-127-5p or its antisense inhibitor (anti-miR-127-5p). MMP-13 protein production was quantified by enzyme-linked immunosorbent assay, and the involvement of miR-127-5p in IL-1β-mediated catabolic effects was examined by immunoblotting. MicroRNA-127-5p binding with the putative site in the 3′-untranslated region (3′-UTR) of MMP-13 messenger RNA (mRNA) was validated by luciferase reporter assay. Results There was a significant reduction in miR-127-5p expression in OA cartilage compared with normal cartilage. Up-regulation of MMP-13 expression by IL-1β was correlated with down-regulation of miR-127-5p expression in human chondrocytes. MicroRNA-127-5p suppressed IL-1β-induced MMP-13 production as well as the activity of a reporter construct containing the 3′-UTR of human MMP-13 mRNA. In addition, mutation of the miR-127-5p binding site in the 3′-UTR of MMP-13 mRNA abolished miR-127-5p-mediated repression of reporter activity. Conversely, treatment with anti-miR-127-5p remarkably increased reporter activity and MMP-13 production. Interestingly, the IL-1β-induced activation of JNK, p38, and NF-κB and expression of MMP-1 and cyclooxygenase 2 were significantly inhibited by miR-127-5p. Conclusion MicroRNA-127-5p is an important regulator of MMP-13 in human chondrocytes and may contribute to the development of OA. [ABSTRACT FROM AUTHOR]

Background Dexamethasone is a potent glucocorticoid with anti-inflammatory effects. Dexamethasone can protect ischemic cardiomyocytes from apoptosis. To apply the anti-apoptotic effect of dexamethasone to ischemic disease gene therapy, dexamethasone-conjugated polyethylenimine (PEI-Dexa) was synthesized and evaluated as an anti-apoptotic gene carrier. Methods PEI-Dexa was synthesized with low molecular weight polyethylenimine (PEI2K, 2 kDa). The transfection efficiency and cytotoxicity of PEI-Dexa were evaluated by luciferase assay and the MTT assay. To evaluate the anti-apoptotic effect, PEI-Dexa/DNA complex was transfected into cells and the cells were treated with H2O2. Cell viability and apoptosis level were measured by the MTT assay and caspase-3 assay, respectively. Results A transfection assay into H9C2 rat cardiomyocytes showed that PEI-Dexa had the highest transfection efficiency at an 8 : 1 weight ratio (PEI-Dexa/DNA). At this ratio, PEI-Dexa had higher transfection efficiency than high molecular polyethylenimine (PEI25K, 25 kDa) and PEI2K. In addition, the cytotoxicity of PEI-Dexa was lower than that of PEI25K. To evaluate the anti-apoptotic effect, PEI-Dexa/pSV-Luc or PEI2K/pSV-Luc was transfected into H9C2 cells and the cells were treated with H2O2. PEI-Dexa was found to reduce caspase-3 activity and increase cell viability compared to PEI2K. Heme oxygenase-1 (HO-1) can protect ischemic cardiomyocytes from apoptosis. Therefore, pSV-HO-1 was cloned and transfected into H9C2 cells using PEI-Dexa. The cells transfected with PEI-Dexa/pSV-HO-1 complex had lower caspase-3 activity and higher viability than the cells transfected with PEI-Dexa/pSV-Luc complex after the H2O2 treatment. Conclusions PEI-Dexa is an efficient gene carrier with an anti-apoptotic effect and may be useful for anti-apoptotic gene therapy in combination with pSV-HO-1. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables such as broccoli, regulates synoviocyte hyperplasia and T cell activation in rheumatoid arthritis (RA)., Methods: Synoviocyte survival was assessed by MTT assay. The levels of Bcl-2, Bax, p53, and pAkt were determined by Western blot analysis. Cytokine concentrations in culture supernatants from mononuclear cells were analyzed by enzyme-linked immunosorbent assay. The in vivo effects of SFN were examined in mice with experimentally induced arthritis., Results: SFN induced synoviocyte apoptosis by modulating the expression of Bcl-2/Bax, p53, and pAkt. In addition, nonapoptotic doses of SFN inhibited T cell proliferation and the production of interleukin-17 (IL-17) and tumor necrosis factor alpha (TNFalpha) by RA CD4+ T cells stimulated with anti-CD3 antibody. Anti-CD3 antibody-induced increases in the expression of retinoic acid-related orphan receptor gammat and T-bet were also repressed by SFN. Moreover, the intraperitoneal administration of SFN to mice suppressed the clinical severity of arthritis induced by injection of type II collagen (CII), the anti-CII antibody levels, and the T cell responses to CII. The production of IL-17, TNFalpha, IL-6, and interferon-gamma by lymph node cells and spleen cells from these mice was markedly reduced by treatment with SFN. Anti-CII antibody-induced arthritis in mice was also alleviated by SFN injection., Conclusion: SFN was found to inhibit synovial hyperplasia, activated T cell proliferation, and the production of IL-17 and TNFalpha by rheumatoid T cells in vitro. The antiarthritic and immune regulatory effects of SFN, which were confirmed in vivo, suggest that SFN may offer a possible treatment option for RA.

Objective: To determine whether intracellular calcineurin (Cn), a calcium-activated phosphatase, regulates the anabolic and catabolic activities of chondrocytes, and is a potential target in the treatment of osteoarthritis (OA)., Methods: CnA expression was examined in cartilage tissue samples and cultured chondrocytes from OA patients, using immunohistochemistry and Western blot analysis, respectively. Concentrations of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the culture supernatants were determined using enzyme-linked immunosorbent assay. Levels of nitric oxide (NO) and type II collagen (CII) were measured using the Griess reaction and Western blot analysis, respectively. In addition, the pathologic role of Cn was examined in an in vivo model in which experimental OA was induced in mice by injecting type VII collagenase into the knee joints., Results: CnA was highly expressed in the chondrocytes of lesional OA cartilage. Cyclosporin A (CSA), a Cn inhibitor, inhibited spontaneous and interleukin-1beta-stimulated production of NO, MMP-1, and MMP-3 in chondrocytes. However, CSA increased the levels of production of CII, TIMP-1, and transforming growth factor beta. Similar changes in MMP-1, NO, and CII expression levels in chondrocytes were observed after the targeted inhibition of Cn by overexpression of calcineurin binding protein 1, a natural Cn antagonist. Moreover, in the mouse model, animals treated with CSA showed a significant decrease in both the extent and the severity of cartilage damage, which were assessed macroscopically and microscopically, compared with vehicle-treated animals., Conclusion: These results suggest that CnA is critically involved in the catabolic and anabolic activities of chondrocytes as well as in the progression of experimental OA. Targeted inhibition of CnA may be an effective treatment strategy for OA.

Objective: To examine the catabolic pathways mediated by Toll-like receptor (TLR) ligands in human osteoarthritic (OA) chondrocytes., Methods: The presence of TLRs in OA and non-OA articular cartilage was analyzed by immunohistochemistry. The regulation of TLR messenger RNA (mRNA) by interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha) was analyzed by reverse transcription-polymerase chain reaction. For stimulation of TLR-2 and TLR-4, chondrocytes were treated with Staphylococcus aureus peptidoglycan and lipopolysaccharides (LPS), respectively. Production of matrix metalloproteinases (MMPs) 1, 3, and 13 and prostaglandin E2 (PGE2) was evaluated by enzyme-linked immunosorbent assay. Production of nitric oxide (NO) was analyzed by the Griess reaction. Regulation of cyclooxygenase 2 protein and phosphorylation of MAPKs (p38, ERK, and JNK) were evaluated by Western blotting or solid-phase kinase assay. NF-kappaB activation was evaluated by electrophoretic mobility shift assay., Results: Expression of TLRs 2 and 4 was up-regulated in lesional areas of OA cartilage. Treatment with IL-1, TNFalpha, peptidoglycan, and LPS all significantly up-regulated TLR-2 mRNA expression in cultured chondrocytes. Production of MMPs 1, 3, and 13 and of NO and PGE2 was significantly increased after treating chondrocytes with either of the TLR ligands. Prolonged culture of cartilage explants with TLR ligands also led to a significant increase in the release of proteoglycan and type II collagen degradation product. Treatment with TLR ligands led to phosphorylation of all 3 MAPKs and activation of NF-kappaB., Conclusion: We found that TLRs are increased in OA cartilage lesions. TLR-2 and TLR-4 ligands strongly induce catabolic responses in chondrocytes. Modulation of TLR-mediated signaling as a therapeutic strategy would require detailed elucidation of the signaling pathways involved.

Objective: To investigate the association of susceptibility and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in an Asian population., Methods: 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., Results: 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])., Conclusion: The DRB1*0405/*0901 heterozygote has the strongest association with RA, suggesting that this heterozygote enhances the susceptibility to RA in Koreans.