Publications by authors named "Hye-Soon Lee"

111 Publications

Genetic variants shape rheumatoid arthritis-specific transcriptomic features in CD4 T cells through differential DNA methylation, explaining a substantial proportion of heritability.

Ann Rheum Dis 2021 07 12;80(7):876-883. Epub 2021 Jan 12.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea

Objective: CD4 T cells have been suggested as the most disease-relevant cell type in rheumatoid arthritis (RA) in which RA-risk non-coding variants exhibit allele-specific effects on regulation of RA-driving genes. This study aimed to understand RA-specific signatures in CD4 T cells using multi-omics data, interpreting inter-omics relationships in shaping the RA transcriptomic landscape.

Methods: We profiled genome-wide variants, gene expression and DNA methylation in CD4 T cells from 82 patients with RA and 40 healthy controls using high-throughput technologies. We investigated differentially expressed genes (DEGs) and differential methylated regions (DMRs) in RA and localised quantitative trait loci (QTLs) for expression and methylation. We then integrated these based on individual-level correlations to inspect DEG-regulating sources and investigated the potential regulatory roles of RA-risk variants by a partitioned-heritability enrichment analysis with RA genome-wide association summary statistics.

Results: A large number of RA-specific DEGs were identified (n=2575), highlighting T cell differentiation and activation pathways. RA-specific DMRs, preferentially located in T cell regulatory regions, were correlated with the expression levels of 548 DEGs mostly in the same topologically associating domains. In addition, expressional variances in 771 and 83 DEGs were partially explained by expression QTLs for DEGs and methylation QTLs (meQTLs) for DEG-correlated DMRs, respectively. A large number of RA variants were moderately to strongly correlated with meQTLs. DEG-correlated DMRs, enriched with meQTLs, had strongly enriched heritability of RA.

Conclusion: Our findings revealed that the methylomic changes, driven by RA heritability-explaining variants, shape the differential expression of a substantial fraction of DEGs in CD4 T cells in patients with RA, reinforcing the importance of a multidimensional approach in disease-relevant tissues.
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http://dx.doi.org/10.1136/annrheumdis-2020-219152DOI Listing
July 2021

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

Ann Rheum Dis 2021 05 3;80(5):632-640. Epub 2020 Dec 3.

Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.

Objective: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.

Methods: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.

Results: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r=-0.242) and non-albumin protein (r=0.238).

Conclusion: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.
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http://dx.doi.org/10.1136/annrheumdis-2020-219209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053352PMC
May 2021

Allele-Specific Quantification of HLA-DRB1 Transcripts Reveals Imbalanced Allelic Expression That Modifies the Amino Acid Effects in HLA-DRβ1.

Arthritis Rheumatol 2021 03 3;73(3):381-391. Epub 2021 Feb 3.

Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.

Objective: HLA association fine-mapping studies have shown the effects of missense variants in HLA-DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA-DRB1 remain poorly understood. Therefore, we investigated the allele-specific expression of HLA-DRB1 and its effect on an HLA-DRβ1 structure-associated trait in RA.

Methods: We quantified the allele-specific expression of each HLA-DRB1 3-field classic allele in 48 Korean RA patients with anti-citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA-DRB1 genotype data to calculate the relative expression strength of multiple HLA-DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA-DRβ1 in ACPA-positive RA was revisited to understand the phenotypic effect of allele-specific expression of HLA-DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala-74 in 2 independent sets of 1,723 Korean RA patients with ACPA.

Results: The relative expression strength was highly allele-specific, causing imbalanced allelic expression in HLA-DRB1 heterozygotes. The association between HLA-DRβ1 Ala-74 and ACPA level in RA was better explained by relative expression dosage of Ala-74 than by the genomic dosage (change in Akaike's information criterion = -6.98). Moreover, the expression variance of Ala-74 in Ala-74 heterozygotes with no genomic variance of Ala-74 was significantly associated with ACPA level (P = 2.26 × 10 ).

Conclusion: Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA-DRB1 into a single model for understanding HLA-DRB1 associations.
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http://dx.doi.org/10.1002/art.41535DOI Listing
March 2021

Frequency of peripheral diseases in Korean patients with ankylosing spondylitis and the effectiveness of adalimumab.

Int J Rheum Dis 2020 Aug 29;23(9):1175-1183. Epub 2020 Jul 29.

Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

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.
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http://dx.doi.org/10.1111/1756-185X.13917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246777PMC
August 2020

Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis.

Ann Rheum Dis 2020 11 28;79(11):1438-1445. Epub 2020 Jul 28.

Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea

Objective: Genome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case-control population.

Methods: We newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.

Results: We identified six new RA-risk loci (, , , , and ) with p<5×10 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.

Conclusion: This study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.
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http://dx.doi.org/10.1136/annrheumdis-2020-217663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569386PMC
November 2020

Deletion at 2q14.3 is associated with worse response to TNF-α blockers in patients with rheumatoid arthritis.

Arthritis Res Ther 2019 08 28;21(1):195. Epub 2019 Aug 28.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, 04763, South Korea.

Background: Structural variations such as copy number variations (CNVs) have a functional impact on various human traits. This study profiled genome-wide CNVs in Korean patients with rheumatoid arthritis (RA) to investigate the efficacy of treatment with TNF-α blockers.

Methods: A total of 357 Korean patients with RA were examined for the efficacy of TNF-α blocker treatment. Disease activity indexes were measured at baseline and 6 months after the treatment. The patients were classified as responders and non-responders based on the change in disease activity indexes according to the EULAR response criteria. CNVs in the same patients were profiled using fluorescence signal intensity data generated by a genome-wide SNP array. The association of CNVs with response to TNF-α blockers was analyzed by multivariate logistic regression accounting for genetic background and clinical factors including body mass index, gender, baseline disease activity, TNF-α blocker used, and methotrexate treatment.

Results: The study subjects varied in their responses to TNF-α blockers and had 286 common CNVs in autosomes. We identified that the 3.8-kb deletion at 2q14.3 in 5% of the subjects was associated with response to TNF-α blockers (1.37 × 10 ≤ P ≤ 4.07 × 10) at a false discovery rate threshold of 5%. The deletion in the identified CNV was significantly more frequent in the non-responders than in the responders, indicating worse response to TNF-α blockers in the deletion carriers. The 3.8-kb deletion at 2q14.3 is located in an intergenic region with the binding sites of two transcription factors, MAFF and MAFK.

Conclusions: This study obtained the CNV landscape of Korean patients with RA and identified the common regional deletion associated with poor response to treatment with TNF-α blockers.
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http://dx.doi.org/10.1186/s13075-019-1983-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714408PMC
August 2019

Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians.

PLoS Genet 2019 04 25;15(4):e1008092. Epub 2019 Apr 25.

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.
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http://dx.doi.org/10.1371/journal.pgen.1008092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504188PMC
April 2019

Prevalence and predictors for sustained remission in rheumatoid arthritis.

PLoS One 2019 19;14(4):e0214981. Epub 2019 Apr 19.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.

Objective: Remission is a key goal in managing rheumatoid arthritis (RA), with sustained remission as the preferred sequelae of short-term remission. However little is known about the predictors of sustained remission for patients reaching remission. Using two independent cohorts, we aimed to evaluate the prevalence and predictors for sustained remission.

Methods: The study cohort consisted of subjects with RA from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and the Korean Observational Study Network for Arthritis (KORONA). We analyzed subjects who reached remission in 2009 with follow up data for two consecutive years. Remission was defined by the Disease Activity Score 28- (DAS28-CRP) of less than 2.6. Sustained remission was defined as three consecutive annual visits in remission. Predictors for sustained remission were identified by multivariate logistic regression analysis.

Results: A total of 465 subjects were in remission in 2009. Sustained remission was achieved by 53 of 92 (57.5%) in BRASS and by 198 of 373 (53.1%) in KORONA. In multivariate analyses, baseline predictors of sustained remission were: disease duration less than 5 years [odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.08-3.58], Modified Health Assessment Questionnaire (MHAQ) score of 0 (OR 1.80, 95% CI 1.18-2.74), and non-use of oral glucocorticoid (OR 1.58, 95% CI 1.01-2.47).

Conclusion: More than half of RA subjects in remission in 2009 remained in remission through 2011. Short disease duration, no disability, and non-use of oral glucocorticoid at baseline were associated with sustained remission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214981PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474583PMC
December 2019

Successful arthroscopic treatment of refractory and complicated popliteal cyst associated with rheumatoid arthritis in combination with osteoarthritis: case series and literature review.

Rheumatol Int 2019 Dec 11;39(12):2177-2183. Epub 2019 Apr 11.

Division of Rheumatology, Department of Internal Medicine, Hanyang University Guri Hospital, 153, Gyeongchunro, Guri, Gyeonggi-do, 11923, South Korea.

Although popliteal cysts are most frequently identified in patients with osteoarthritis (OA), they may occur in patients with rheumatoid arthritis (RA), in which serious complicated cases such as cyst rupture can be developed. The objective of this study was to report four patients with RA (six knees) in combination with OA with a brief review of literature of previous similar published cases. This is a retrospective review of case records of patients with refractory and/or complicated popliteal cysts, who have successfully treated with arthroscopic intervention. We suggest that arthroscopic interventions such as radical debridement, synovectomy, biomechanical valve excision, and/or cystectomy should be considered in patients with refractory and complicated popliteal cysts associated with RA or RA in combination with OA.
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http://dx.doi.org/10.1007/s00296-019-04278-9DOI Listing
December 2019

Simplified disease activity changes in real-world practice: a nationwide observational study of seropositive rheumatoid arthritis patients with moderate-to-high disease activity.

Korean J Intern Med 2020 01 28;35(1):231-239. Epub 2019 Jan 28.

Division of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

Background/aims: The objective of this study was to compare changes in the simplified disease activity index (SDAI) between biologic (b) and conventional (c) disease-modifying antirheumatic drugs (DMARD) users with seropositive rheumatoid arthritis (RA) in daily clinical practice.

Methods: This was a nationwide multicenter observational study. Patients who had three or more active joint counts and abnormal inf lammatory marker in blood test were enrolled. The selection of DMARDs was determined by the attending rheumatologist. Clinical parameters, laboratory findings, and Health Assessment Questionnaire (HAQ) scores were obtained at baseline and at 6 and 12 months. Serial SDAI changes and clinical remission rate at 6 and 12 months were assessed.

Results: A total of 850 patients participated in this study. The mean baseline SDAI score in bDMARD group was higher than that in cDMARD group (32.08 ± 12.98 vs 25.69 ± 10.97, p < 0.0001). Mean change of SDAI at 12 months was -19.0 in the bDMARD group and -12.6 in the cDMARD group (p < 0.0001). Clinical remission rates at 12 months in bDMARD and cDMARD groups were 15.4% and 14.6%, respectively. Patient global assessment and HAQ at 12 months were also significantly improved in both groups. Multivariate logistic regression showed that baseline HAQ score was the most notable factor associated with remission.

Conclusion: There was a significant reduction in SDAI within 12 months after receiving DMARDs in Korean seropositive RA patients irrespective of bDMARD or cDMARD use in real-world practice. Clinical remission was achieved in those with lower baseline HAQ scores.
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http://dx.doi.org/10.3904/kjim.2018.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960052PMC
January 2020

Association between brain-derived neurotrophic factor gene polymorphisms and fibromyalgia in a Korean population: a multicenter study.

Arthritis Res Ther 2018 10 3;20(1):220. Epub 2018 Oct 3.

Division of Rheumatology, Department of Internal Medicine, Chonnam National University Medical School and Hospital, 42 Jebong-ro, Dong-gu, Gwangju, 61469, Republic of Korea.

Background: Several lines of evidence imply that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of fibromyalgia (FM); in this regard, patients with FM have altered blood and cerebrospinal fluid levels of BDNF. In this study, we explored the association between BDNF gene polymorphisms and FM susceptibility and the severity of symptoms.

Methods: In total, 409 patients with FM and 423 healthy controls in 10 medical centers were enrolled from the Korean nationwide FM survey. The alleles and genotypes at 10 positions in the BDNF gene were genotyped.

Results: The allele and genotype frequencies of BDNF rs11030104 differed significantly between the patients with FM and the controls (P = 0.031). The GG genotype of rs11030104 had a protective effect against FM (P = 0.016), and the G allele of rs11030104 was negatively associated with the presence of FM compared with the A allele (P = 0.013). In comparison, although the allele and genotype frequencies of BDNF rs12273539 did not differ between the two groups, the TT genotype of BDNF rs12273539 was associated with susceptibility to FM (P = 0.038). Haplotype analyses implied that some BDNF haplotypes have a protective effect against FM. Finally, several genotypes and haplotypes of the BDNF gene contributed to specific symptoms of FM.

Conclusions: This study is the first to evaluate the associations between BDNF gene polymorphisms and FM. Our results imply that some BDNF single-nucleotide polymorphisms and haplotypes are associated with susceptibility to, and contribute to the symptoms of, FM.
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http://dx.doi.org/10.1186/s13075-018-1726-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235218PMC
October 2018

Efficacy and safety of mycophenolate mofetil and tacrolimus combination therapy in patients with lupus nephritis: a nationwide multicentre study.

Clin Exp Rheumatol 2019 Jan-Feb;37(1):89-96. Epub 2018 Jun 14.

Division of Rheumatology, Department of Internal Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.

Objectives: Recent studies have shown that a combination treatment of mycophenolate mofetil (MMF) and tacrolimus (TAC) may be an option for lupus nephritis (LN) patients that do not adequately respond to initial treatment. We evaluated the efficacy and safety of the combination treatment of MMF and TAC in LN patients with suboptimal response to prior MMF or TAC treatments.

Methods: In this multicentre study, we retrospectively enrolled 62 patients with class III, IV, or V LN who inadequately responded to MMF or TAC treatment. Those patients were then treated with a combination of MMF and TAC for 6 months. The primary outcome was complete remission (CR) at 6 months, and secondary outcomes included overall response and adverse events.

Results: After 6 months of treatment with the drug combination, CR was achieved in 14 of 62 patients (22.6%), and 35 (56.5%) patients responded. A significant reduction in proteinuria and lupus disease activity score was observable after 3 months. After 1 year, the CR rate increased to 36.4% (20 of 55 patients), and the overall response rate (n=38, 69.1%) also increased from 6 months. Twenty-one patients reported 29 adverse events, including severe infection requiring hospitalisation (n=3, 10.3%), infection not requiring hospitalisation (n=2, 6.9%), and herpes zoster (n=4, 13.8%).

Conclusions: Our findings suggest that a combined MMF and TAC treatment, with a favourable adverse-event profile, may be a beneficial option for LN patients with inadequate response to either MMF or TAC treatments.
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May 2019

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

Hum Mol Genet 2018 07;27(13):2392-2404

Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.
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http://dx.doi.org/10.1093/hmg/ddy140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005081PMC
July 2018

Factors associated with quality of life and functional disability among rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs for at least 6 months.

Int J Rheum Dis 2018 May 5;21(5):1001-1009. Epub 2016 Nov 5.

Outcomes Research/Real World Data Team Corporate Affairs and Health & Value Division, Pfizer Pharmaceuticals Korea Limited, Seoul, South Korea.

Aim: To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying anti-rheumatic drugs (DMARDs) for at least 6 months, and to identify factors associated with poor health-related outcomes.

Method: A total of 2000 RA patients aged > 20 years, treated with DMARDs for at least 6 months, and signed informed consent, were enrolled in this non-interventional, multicenter, cross-sectional observational study from December 2012 to June 2013. Health-related quality of life (HRQoL) was measured using EuroQuol 5D (EQ-5D) and functional disability was measured using the Korean Health Assessment Questionnaire (KHAQ). Univariate and multivariate linear regression analyses were used to determine the association between patient characteristics and patient-reported outcomes (PROs).

Results: Of all RA patients, 84% were female, patients with low Disease Activity Score of 28 joints erythrocyte sedimentation rate (DAS-28-ESR < 3.2) was 54%, while moderate (DAS-28-ESR 3.2-5.1) and high disease activity score (DAS-28-ESR > 5.1) were 38% and 7.6%, respectively. Mean EQ-5D index score and KHAQ score were 0.6 ± 0.28 and 0.7 ± 0.67, respectively. In multivariate analysis with both PROs, average HRQoL and functional disability score appeared to be worse in persons with older age compared to younger age (P < 0.001), and worse in females compared to males (P < 0.001). Compared to patients having lower DAS (< 3.2), those with moderate and highest DAS (3.2-5.1 and > 5.1) had worse outcome measures (P < 0.001).

Conclusion: In this study, higher DAS was one of the most influential factors for poor PROs among all other factors. Therefore, we could suggest appropriate treatment approaches according to DAS along with other significantly associated factors with PROs in the early stage of RA.
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http://dx.doi.org/10.1111/1756-185X.12915DOI Listing
May 2018

Outcome and predictors of renal survival in patients with lupus nephritis: Comparison between cyclophosphamide and mycophenolate mofetil.

Int J Rheum Dis 2018 May 2;21(5):1031-1039. Epub 2018 Apr 2.

Division of Rheumatology, Department of Internal Medicine, Hanyang University Guri Hospital, Guri-si, Korea.

Aim: To compare renal outcomes between cyclophosphamide (CYC) and mycophenolate mofetil (MMF), and attempt to identify a predictor of renal survival.

Methods: A total of 99 patients with class III-V lupus nephritis (LN) and treated with CYC or MMF were enrolled. The remission rate and predictors of poor renal outcomes in LN were assessed.

Results: The mean age at LN diagnosis was 31.7 years. The baseline characteristics of the two groups were similar except for the chronicity index (3.1 ± 2.4 and 2.3 ± 0.8 for CYC and MMF, respectively, P = 0.007). The overall remission rate was 76.8% and 77.7% after 6 and 12 months, respectively, with no significant difference between the two groups at these time points. After a median follow-up of 36 months (interquartile range 12-60), eight (8.1%) patients had chronic kidney disease, four (4.1%) were dialyzed permanently, and seven (7.1%) suffered a relapse, with no significant difference in these final outcomes between the two groups. Adverse events included infection (CYC group), and rash and neutropenia (MMF group), with no significant difference in frequency between the two groups. Failure of induction therapy (hazards ratio [HR] = 10.626, P = 0.022) and the creatinine level at diagnosis of LN (HR = 8.397, P = 0.007) were significantly associated with renal survival adjusted for age at LN diagnosis, disease duration and proteinuria.

Conclusion: Response to current induction therapy for LN was favorable, and 6 months response following induction therapy was the most important predictor for renal survival.
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http://dx.doi.org/10.1111/1756-185X.13274DOI Listing
May 2018

Factors associated with time to diagnosis from symptom onset in patients with early rheumatoid arthritis.

Korean J Intern Med 2019 Jul 15;34(4):910-916. Epub 2017 Dec 15.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

Background/aims: To identify the factors associated with time to diagnosis after symptom onset in patients with early rheumatoid arthritis (RA).

Methods: Early RA patients with ≤ 1 year of disease duration in the KORean Observational study Network for Arthritis (KORONA) database were included in this analysis. Patients were further divided into two groups according to the time to diagnosis from symptom onset: the early diagnosis group (time to diagnosis ≤ 1 year) and the late diagnosis group (time to diagnosis > 1 year). Using the multivariable regression model, we identified factors associated with early diagnosis.

Results: Among 714 early RA patients, 401 patients (56.2%) and 313 patients (43.8%) were included in the early diagnosis and late diagnosis groups, respectively. The mean disease duration was 0.47 years in the early diagnosis group and 0.45 years in the late diagnosis group. In multivariable model analysis, greater age at onset (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02 to 1.05), high school education or higher (OR, 1.68; 95% CI, 1.14 to 2.47), higher income (OR, 1.48; 95% CI, 1.05 to 2.08), and initial small joint involvement (OR, 1.42; 95% CI, 1.02 to 1.98) were factors associated with early diagnosis. At diagnosis, disease activity scores using 28 joints on diagnosis (3.81 ± 1.44 vs. 3.82 ± 1.42, p = 0.92) and functional disability (0.65 ± 0.61 vs. 0.57 ± 0.62, p = 0.07) did not different between the two groups. However, hand joint erosion on X-ray (37.8% vs. 25.6%, p < 0.01) was more common in the late diagnosis group than the early diagnosis group.

Conclusion: Older onset age, higher educational level and income, and initial small joint involvement were positive factors for early diagnosis of RA.
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http://dx.doi.org/10.3904/kjim.2017.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610196PMC
July 2019

Biological function integrated prediction of severe radiographic progression in rheumatoid arthritis: a nested case control study.

Arthritis Res Ther 2017 Oct 25;19(1):244. Epub 2017 Oct 25.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.

Background: Radiographic progression is reported to be highly heritable in rheumatoid arthritis (RA). However, previous study using genetic loci showed an insufficient accuracy of prediction for radiographic progression. The aim of this study is to identify a biologically relevant prediction model of radiographic progression in patients with RA using a genome-wide association study (GWAS) combined with bioinformatics analysis.

Methods: We obtained genome-wide single nucleotide polymorphism (SNP) data for 374 Korean patients with RA using Illumina HumanOmni2.5Exome-8 arrays. Radiographic progression was measured using the yearly Sharp/van der Heijde modified score rate, and categorized in no or severe progression. Significant SNPs for severe radiographic progression from GWAS were mapped on the functional genes and reprioritized by post-GWAS analysis. For robust prediction of radiographic progression, tenfold cross-validation using a support vector machine (SVM) classifier was conducted. Accuracy was used for selection of optimal SNPs set in the Hanyang Bae RA cohort. The performance of our final model was compared with that of other models based on GWAS results and SPOT (one of the post-GWAS analyses) using receiver operating characteristic (ROC) curves. The reliability of our model was confirmed using GWAS data of Caucasian patients with RA.

Results: A total of 36,091 significant SNPs with a p value <0.05 from GWAS were reprioritized using post-GWAS analysis and approximately 2700 were identified as SNPs related to RA biological features. The best average accuracy of ten groups was 0.6015 with 85 SNPs, and this increased to 0.7481 when combined with clinical information. In comparisons of the performance of the model, the 0.7872 area under the curve (AUC) in our model was superior to that obtained with GWAS (AUC 0.6586, p value 8.97 × 10) or SPOT (AUC 0.7449, p value 0.0423). Our model strategy also showed superior prediction accuracy in Caucasian patients with RA compared with GWAS (p value 0.0049) and SPOT (p value 0.0151).

Conclusions: Using various biological functions of SNPs and repeated machine learning, our model could predict severe radiographic progression relevantly and robustly in patients with RA compared with models using only GWAS results or other post-GWAS tools.
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http://dx.doi.org/10.1186/s13075-017-1414-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655942PMC
October 2017

Impact of interstitial lung disease on mortality of patients with rheumatoid arthritis.

Rheumatol Int 2017 Oct 26;37(10):1735-1745. Epub 2017 Jul 26.

Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.

To identify the prevalence of interstitial lung disease (ILD) in Korean patients with rheumatoid arthritis (RA) and assess its effect on mortality. A total of 3555 patients with RA, with chest X-ray or chest computed tomography (CT) data at enrollment were extracted from the KORean Observational study Network for Arthritis cohort, a nationwide prospective cohort for patients with RA in Korea. The patients were classified into two groups: (1) an ILD group by chest X-ray or chest CT scan, and (2) a non-ILD group by these modalities. After comparing the characteristics of the groups at enrollment, mortalities were compared using the log-rank test. To explore the impact of ILD on mortality, Cox proportional hazard models were used. Sixty-four patients (1.8%) were identified with ILD. Male and older patients were more common in the ILD group. During a mean follow-up of 24 months, 6 patients (9.4%) in the ILD group and 25 patients (0.7%) in the non-ILD group died; the survival rate was significantly worse in the ILD group (p < 0.01). On adjusted analysis, ILD was significantly associated with increased mortality (HR 7.89, CI 3.16-19.69, p < 0.01); the risk of death in patients with ILD was even higher than in patients with cardiovascular disease (CVD, HR 4.10, CI 1.79-9.37, p < 0.01). The prevalence of ILD was 1.8% in Korean patients with RA. ILD is a major risk factor for mortality in patients with RA.
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http://dx.doi.org/10.1007/s00296-017-3781-7DOI Listing
October 2017

Association of CD8 T-cells with bone erosion in patients with rheumatoid arthritis.

Int J Rheum Dis 2018 Feb 16;21(2):440-446. Epub 2017 May 16.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

Aim: Bone erosion is a major problem worsening quality of rheumatoid arthritis (RA) patients' lives. However, causal factors responsible for bone erosion in RA have remained unclear. We aimed to examine genetic variants conferring bone erosion in RA using a Korean genome-wide association study (GWAS) and to search for possible biological mechanisms underlying the development of bone erosion.

Method: We obtained genome-wide single nucleotide polymorphism (SNP) data for 711 Korean RA patients using Illumina HapMap 550v3/660W arrays. Associations between SNPs and bone erosion status based on the Steinbrocker staging system were examined using multivariate logistic regression. Cell-type-specific enrichment of the epigenomic chromatin annotation H3K4me3 at the bone erosion associated variants was further investigated using National Institute of Health Roadmap Epigenomics data.

Results: As we tested the associations between 439 289 SNPs and bone erosion in 385 patients with erosive RA and 326 with non-erosive RA, none of the tested SNPs reached the genome-wide significance threshold, although many loci showed modest genetic effect on bone erosion status with suggestive association (e.g., rs2741200 [P = 3.75 × 10 ] in the SLA-TG locus and rs12422918 [P = 4.13 × 10 ] in SRGAP1). However, the top-ranked SNPs and their linked proxies, which were mostly located in non-coding variants, were significantly co-localized with the highly tissue-specific regulatory marker H3K4me3 in CD8 memory T-cells (P = 0.014).

Conclusion: Although, there was no large-effect variants associated with bone erosion in our GWAS, we have shown that CD8 memory T-cells may have relevance with bone erosion in patients with RA through the analysis of ChiP-seq data.
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http://dx.doi.org/10.1111/1756-185X.13090DOI Listing
February 2018

Predictors of severe radiographic progression in patients with early rheumatoid arthritis: A Prospective observational cohort study.

Int J Rheum Dis 2017 Oct 5;20(10):1437-1446. Epub 2017 Mar 5.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

Aim: To identify predictors of severe radiographic progression in patients with early rheumatoid arthritis (ERA).

Methods: A total of 374 patients with ERA were selected from a Korean prospective cohort. Based on their annual Sharp/Van der Heijde modified score changes (ΔSHS/year), patients were classified into severe and no progression groups. Predictors of severe progression were evaluated using a multivariable logistic regression.

Results: After a mean follow-up duration of 4.2 years, the median (interquartile range) ΔSHS/year were 6.3 (4.4-10.2) and 0 (0-0) in the severe and no progression groups, respectively. Multivariable regression model revealed that Health Assessment Questionnaire (HAQ) score (odds ratio [OR] = 2.17), anticyclic citrullinated peptide antibody (OR = 3.44), body mass index (BMI; OR = 0.88), 6-month cumulative erythrocyte sedimentation rate (OR = 1.01) and baseline SHS (OR = 1.07) were independent predictors of severe progression. A model incorporating all five predictors satisfactorily predicted severe progression, with an area under the curve of 0.80. Baseline SHS was the predictor with the highest contribution to the predictive power of the final model (38%).

Conclusions: Our predictive model composed of five clinical predictors showed high discriminative ability between severe and no radiographic progression in patients with ERA. Among them, baseline SHS was the strongest predictor. Also, low BMI in Korean patients with ERA have a high risk of severe radiographic progression, as has previously been found for Caucasians.
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http://dx.doi.org/10.1111/1756-185X.13054DOI Listing
October 2017

Characteristics and outcomes of rheumatoid arthritis patients who started biosimilar infliximab.

Rheumatol Int 2017 Jun 18;37(6):1007-1014. Epub 2017 Feb 18.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.

To compare the characteristics of rheumatoid arthritis (RA) patients receiving either biosimilar or originator infliximab and to identify the effectiveness and safety of biosimilar infliximab in RA patients in real-world practice. RA patients who started either biosimilar or originator infliximab were selected using the prospective biologic disease-modifying anti-rheumatic drugs (DMARDs) registry: BIOlogics Pharmacoepidemiologic StudY (BIOPSY). Baseline characteristics of the two groups were compared, and short-term treatment outcomes, including DAS28-ESR and HAQ-DI scores, were compared after initiation of biosimilar or originator infliximab. The drug retention rates of the two groups were also compared. A total of 100 RA patients, 55 biosimilar, and 45 originator infliximab users were included in this analysis. Baseline characteristics of age, disease duration, and previous or current medications were similar in the two groups. Baseline DAS28-ESR was higher in the originator infliximab group (6.3 ± 1.1 vs. 5.8 ± 1.1, p = 0.02). The early DAS28-ESR remission rates observed 7.9 ± 1.8 months after starting biosimilar and originator infliximab were 15.0 and 25.0%, respectively (p = 0.47). The change in HAQ-DI did not differ between the two groups (0.4 ± 0.7 vs. 0.4 ± 0.8, p = 0.94). Patients treated with biosimilar infliximab in clinical practice had lower disease activity at the start of treatment than those receiving originator infliximab. Biosimilar infliximab was well-tolerated, safe, and of similar clinical effectiveness to originator infliximab. Larger number of patient and longer follow-up data will be needed to confirm the effectiveness and safety of biosimilar infliximab in clinical practice.
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http://dx.doi.org/10.1007/s00296-017-3663-zDOI Listing
June 2017

Determinants of quality of life in patients with fibromyalgia: A structural equation modeling approach.

PLoS One 2017 3;12(2):e0171186. Epub 2017 Feb 3.

Division of Rheumatology, Department of Internal Medicine, Chonnam National University Hospital & Medical School, Gwangju, Korea.

Objective: Health-related quality of life (HRQOL) in patients with fibromyalgia (FM) is lower than in patients with other chronic diseases and the general population. Although various factors affect HRQOL, no study has examined a structural equation model of HRQOL as an outcome variable in FM patients. The present study assessed relationships among physical function, social factors, psychological factors, and HRQOL, and the effects of these variables on HRQOL in a hypothesized model using structural equation modeling (SEM).

Methods: HRQOL was measured using SF-36, and the Fibromyalgia Impact Questionnaire (FIQ) was used to assess physical dysfunction. Social and psychological statuses were assessed using the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), the Arthritis Self-Efficacy Scale (ASES), and the Social Support Scale. SEM analysis was used to test the structural relationships of the model using the AMOS software.

Results: Of the 336 patients, 301 (89.6%) were women with an average age of 47.9±10.9 years. The SEM results supported the hypothesized structural model (χ2 = 2.336, df = 3, p = 0.506). The final model showed that Physical Component Summary (PCS) was directly related to self-efficacy and inversely related to FIQ, and that Mental Component Summary (MCS) was inversely related to FIQ, BDI, and STAI.

Conclusions: In our model of FM patients, HRQOL was affected by physical, social, and psychological variables. In these patients, higher levels of physical function and self-efficacy can improve the PCS of HRQOL, while physical function, depression, and anxiety negatively affect the MCS of HRQOL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171186PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291376PMC
August 2017

A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases.

Nat Genet 2017 Mar 30;49(3):433-437. Epub 2017 Jan 30.

Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47 subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (P = 3.1 × 10), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjögren's syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.
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http://dx.doi.org/10.1038/ng.3782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400098PMC
March 2017

Comparative effectiveness of treatment options after conventional DMARDs failure in rheumatoid arthritis.

Rheumatol Int 2017 Jun 28;37(6):975-982. Epub 2017 Jan 28.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, 04763, South Korea.

Objective: To compare the clinical effectiveness of two treatment strategies for active rheumatoid arthritis (RA) refractory to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs): starting TNF inhibitors (TNFIs) or changing csDMARDs.

Methods: We used two nationwide Korean RA registries for patient selection. TNFI users were selected from the BIOPSY, which is an inception cohort of RA patients starting biologic DMARDs. As a control group, we selected RA patients with moderate or high disease activity from the KORONA database whose treatment was changed to other csDMARDs. After comparing baseline characteristics between the two groups in either unmatched or propensity score matched cohorts, we compared potential differences in the 1-year remission rate as a primary outcome and changes in HAQ-DI and EQ-5D scores as secondary outcomes.

Results: A total of 356 TNFI starters and 586 csDMARD changers were identified from each registry as unmatched cohorts, and 294 patients were included in the propensity score matched cohort. In the intention-to-treat analysis, TNFI starters had higher 1-year remission rates than csDMARD changers in both unmatched (19.1 vs. 18.4%, p < 0.01) and matched cohorts (19.7 vs. 15.0%, p < 0.01). In per protocol analysis, TNFI starters had much higher remission rates in unmatched (37.2 vs. 28.0%, p = 0.04) and matched cohorts (35.4 vs. 19.1%, p = 0.04). However, in matched cohorts, no significant differences were observed between two groups in HAQ-DI and EQ-5D scores.

Conclusions: We compared the clinical effectiveness of the two treatment strategies for active RA refractory to csDMARDs. TNFI starters showed higher 1-year remission rates than csDMARD changers.
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http://dx.doi.org/10.1007/s00296-016-3649-2DOI Listing
June 2017

Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci.

Hum Mol Genet 2017 03;26(6):1205-1216

Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.
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http://dx.doi.org/10.1093/hmg/ddx026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731438PMC
March 2017

Factors Contributing to Discordance between the 2011 ACR/EULAR Criteria and Physician Clinical Judgment for the Identification of Remission in Patients with Rheumatoid Arthritis.

J Korean Med Sci 2016 Dec;31(12):1907-1913

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

Remission is a primary end point of in clinical practice and trials of treatments for rheumatoid arthritis (RA). The 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria were developed to provide a consensus definition of remission. This study aimed to assess the concordance between the new remission criteria and the physician's clinical judgment of remission and also to identify factors that affect the discordance between these two approaches. A total of 3,209 patients with RA were included from the KORean Observational Study Network for Arthritis (KORONA) database. The frequency of remission was evaluated based on each approach. The agreement between the results was estimated by Cohen's kappa (κ). Patients with remission according to the 2011 ACR/EULAR criteria (i.e. the Boolean criteria) and/or physician judgment (n = 855) were divided into three groups: concordant remission, the Boolean criteria only, and physician judgment only. Multinomial logistic regression analysis was used to identify factors responsible for the assignment of patients with remission to one of the discordant groups rather than the concordant group. The remission rates using the Boolean criteria and physician judgment were 10.5% and 19.9%, respectively. The agreement between two approaches for remission was low (κ = 0.226) and the concordant remission rate was only 5.5% (n = 177). Pain affected classification in both discordant groups, whereas fatigue was associated with remission only by physician clinical judgment. The Boolean criteria were more stringent than clinical judgment. Patient subjective symptoms such as pain and fatigue were associated with discordance between the two approaches.
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http://dx.doi.org/10.3346/jkms.2016.31.12.1907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102853PMC
December 2016

Update on the genetic architecture of rheumatoid arthritis.

Nat Rev Rheumatol 2017 Jan 4;13(1):13-24. Epub 2016 Nov 4.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.

Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.
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http://dx.doi.org/10.1038/nrrheum.2016.176DOI Listing
January 2017

Impact of early diagnosis on functional disability in rheumatoid arthritis.

Korean J Intern Med 2017 Jul 13;32(4):738-746. Epub 2016 Sep 13.

Department of Rheumatology, Hospital for Rheumatic Diseases, Hanyang University College of Medicine, Seoul, Korea.

Background/aims: To determine whether early diagnosis is beneficial for functional status of various disease durations in rheumatoid arthritis (RA) patients.

Methods: A total of 4,540 RA patients were enrolled as part of the Korean Observational Study Network for Arthritis (KORONA). We defined early diagnosis as a lag time between symptom onset and RA diagnosis of ≤ 12 months, whereas patients with a longer lag time comprised the delayed diagnosis group. Demographic characteristics and outcomes were compared between early and delayed diagnosis groups. Logistic regression analyses were performed to identify the impact of early diagnosis on the development of functional disability in RA patients.

Results: A total of 2,597 patients (57.2%) were included in the early diagnosis group. The average Health Assessment Questionnaire-Disability Index (HAQ-DI) score was higher in the delayed diagnosis group (0.64 ± 0.63 vs. 0.70 ± 0.66, < 0.01), and the proportion of patients with no functional disability (HAQ = 0) was higher in the early diagnosis group (22.9% vs. 20.0%, = 0.02). In multivariable analyses, early diagnosis was independently associated with no functional disability (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.01 to 1.40). In a subgroup analysis according to disease duration, early diagnosis was associated with no functional disability in patients with disease duration < 5 years (OR, 1.37; 95% CI, 1.09 to 1.72) but not in patients with longer disease duration (for 5 to 10 years: OR, 1.07; 95% CI, 0.75 to 1.52; for ≥ 10 years: OR, 0.92; 95% CI, 0.65 to 1.28).

Conclusions: Early diagnosis is associated with no functional disability, especially in patients with shorter disease duration.
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http://dx.doi.org/10.3904/kjim.2015.364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511933PMC
July 2017

Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis.

Sci Rep 2016 06 8;6:27563. Epub 2016 Jun 8.

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.

Considerable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran's homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (PHeterogeneity = 9.6 × 10(-9) at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and PMeta = 4.2 × 10(-13) in Asians; ORMeta = 1.00 and PMeta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
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http://dx.doi.org/10.1038/srep27563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897688PMC
June 2016
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