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1.  Implementing the Use of Rapid HIV Tests in Public Health Centers in Seoul: Results of a Pilot Project, 2014 
Journal of Korean Medical Science  2016;31(3):467-469.
To determine whether rapid HIV tests in public health centers might encourage voluntary HIV testing, a pilot project was conducted in four selected public health centers in Seoul, 2014. During the period April 10 to November 28 of pilot project, 3,356 rapid tests were performed, and 38 were confirmed as positive. The monthly average numbers of voluntary HIV tests and HIV-positive cases were up to nine-fold and six-fold larger, respectively, than those of the period before application of the rapid HIV test. Among 2,051 examinees that completed questionnaires, 90.3% were satisfied. In conclusion, the use of rapid HIV tests in public health centers promoted voluntary HIV testing and was satisfactory for examinees.
PMCID: PMC4779875  PMID: 26955251
HIV; Rapid HIV Test; Anonymous HIV Test; Public Health Center; Seoul Metropolitan City
2.  Imputing Variants in HLA-DR Beta Genes Reveals That HLA-DRB1 Is Solely Associated with Rheumatoid Arthritis and Systemic Lupus Erythematosus 
PLoS ONE  2016;11(2):e0150283.
The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE.
PMCID: PMC4769216  PMID: 26919467
3.  The frequency of and risk factors for osteoporosis in Korean patients with rheumatoid arthritis 
The aim of this study was to investigate the prevalence of osteoporosis in rheumatoid arthritis (RA) patients and to analyze the risk factors in these patients using the KORean Observational study Network for Arthritis (KORONA) database.
Among the RA patients in the KORONA who were recruited between July 2009 and December 2011, postmenopausal women with bone mineral density (BMD) results within one year from the time of KORONA enrollment were included in this study. The baseline characteristics of patients in three groups, defined by BMD results, were compared. The BMD measurement rates and prevalence of osteoporosis in the study patients were calculated in accordance with age and gender subgroups. Multivariable logistic regression analysis was used to explore the association between osteoporosis and demographics and disease-related risk factors.
Of 1322 postmenopausal woman patients with RA in whom BMD was measured within one year of study enrollment, 619 patients (46.8 %) were in the osteoporosis group (T-score ≤ −2.5 SD). RA patients with osteoporosis had a higher frequency of previous fractures than those in other groups, especially fractures of the femur (p = 0.004) and wrist (p = 0.042). Advanced age (≥70 years; OR = 2.28, 95 % CI: 1.40–3.58), lower body mass index (<25; OR = 2.14, 95 % CI:1.52–3.02), longer disease duration (≥10 years; OR = 1.46, 95 % CI: 1.07–2.00), higher cumulative glucocorticoid dose (OR = 1.03, 95 % CI: 1.01–1.05), and higher Health Assessment Questionnaire score (OR = 1.37, 95 % CI:1.11–1.69) were independent risk factors for osteoporosis.
A large percentage (90.8 %) of RA patients enrolled in the KORONA cohort had osteoporosis and osteopenia. Nevertheless, BMD measurement rates in this population remained low, despite high risk groups of fractures.
PMCID: PMC4765070  PMID: 26912147
Osteoporosis; Rheumatoid arthritis; Frequency; Risk factors
4.  Patients Presenting with Advanced Human Immunodeficiency Virus Disease: Epidemiological Features by Age Group 
Journal of Korean Medical Science  2016;31(2):178-182.
We explored factors influencing presentation with advanced human immunodeficiency virus (HIV) disease by age group. Data were derived from a city-wide cross-sectional survey of 759 HIV-infected adults living in Seoul, Korea. The significance of each observed factor was assessed via multivariate logistic regression. Of subjects aged 20-34 years, lower educational level had a positive influence on presentation with advanced HIV disease (adjusted odds ratio [aOR], 2.43; 95% confidence interval [CI], 1.36-4.34); those recently diagnosed with HIV were more likely to be presented with advanced HIV disease (aOR, 3.17; 95% CI, 0.99-10.2). Of the subjects aged 35-49 years, those w ith advanced HIV disease were more likely to have been diagnosed during health check-ups (aOR, 2.91; 95% CI, 1.15-7.32) or via clinical manifestations (aOR, 3.61; 95% CI, 1.39-9.36). Of the subjects aged ≥ 50 years, presentation with advanced HIV disease was significantly more common in older subjects (aOR per increment of 5 years, 2.06; 95% CI, 1.32-3.23) and less common among individuals diagnosed with HIV in 2000-2006 (aOR, 0.18; 95% CI, 0.04-0.83). In conclusion, a lower educational level in younger subjects and more advanced age in older subjects positively influence the presentation of advanced HIV disease.
Graphical Abstract
PMCID: PMC4729495  PMID: 26839469
HIV; Acquired Immune Deficiency Syndrome; Late Presentation; Early Detection; Seoul Metropolitan City; Low Education; Old Age
5.  High-Density Genotyping of Immune Loci in Koreans and Europeans Identifies Eight New Rheumatoid Arthritis Risk Loci 
A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data.
We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples.
We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs.
This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
PMCID: PMC4467986  PMID: 24532676
Rheumatoid arthritis; Gene polymorphism; Anti-CCP
6.  Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry 
The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice.
This prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis.
Patients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37).
The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0583-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4384380  PMID: 25880658
7.  Effects of Age on Arterial Stiffness and Blood Pressure Variables in Patients with Newly Diagnosed Untreated Hypertension 
Korean Circulation Journal  2015;45(1):44-50.
Background and Objectives
To investigate the impact of age on arterial stiffness and blood pressure (BP) variables in newly diagnosed untreated hypertension (HT).
Subjects and Methods
A total of 144 patients with newly diagnosed untreated HT were divided into two groups: young group (age ≤50 years, n=71), and old group (age >50 years, n=73). BP variables were measured on office or 24 hours ambulatory BP monitoring (ABPM). Parameters of arterial stiffness were measured on pulse wave velocity (PWV). Pulse wave analysis (PWA) was compared.
Although office BP and pulse pressure (PP) were significantly (p<0.05) higher in the young group than in the old group, BP and PP on ABPM were not significantly different. Central systolic BP and PP, augmentation pressure, augmentation index on PWA, and PWV were significantly higher or faster in the old group compared to that in the young group. Age showed significant positive correlation with both PWV and PWA variables in the young group with HT. However, age only showed significant positive correlation with PWV in the old group with HT. In the young group with HT, PWA variable showed better correlation with age than PWV.
Considering BP levels on ABPM, office BP is prone to be overestimated in young patients with HT. Parameters of arterial stiffness measured by PWV and PWA were more affected by age rather than by BP level in patients with HT. Therefore, PWA variable might be a more sensitive marker of arterial stiffness in young patients with HT. However, PWV might be a better marker for old patients with HT.
PMCID: PMC4310979  PMID: 25653703
Hypertension; Vascular stiffness; Aging
8.  Predictors of Viral Pneumonia in Patients with Community-Acquired Pneumonia 
PLoS ONE  2014;9(12):e114710.
Viruses are increasingly recognized as major causes of community-acquired pneumonia (CAP). Few studies have investigated the clinical predictors of viral pneumonia, and the results have been inconsistent. In this study, the clinical predictors of viral pneumonia were investigated in terms of their utility as indicators for viral pneumonia in patients with CAP.
Adult patients (≥18 years old) with CAP, tested by polymerase chain reaction (PCR) for respiratory virus, at two teaching hospitals between October 2010 and May 2013, were identified retrospectively. Demographic and clinical data were collected by reviewing the hospital electronic medical records.
During the study period, 456 patients with CAP were identified who met the definition, and 327 (72%) patients were tested using the respiratory virus PCR detection test. Viral pneumonia (n = 60) was associated with rhinorrhea, a higher lymphocyte fraction in the white blood cells, lower serum creatinine and ground-glass opacity (GGO) in radiology results, compared to non-viral pneumonia (n = 250) (p<0.05, each). In a multivariate analysis, rhinorrhea (Odd ratio (OR) 3.52; 95% Confidence interval (CI), 1.58–7.87) and GGO (OR 4.68; 95% CI, 2.48–8.89) were revealed as independent risk factors for viral pneumonia in patients with CAP. The sensitivity, specificity, positive- and negative-predictive values (PPV and NPV) of rhinorrhea were 22, 91, 36 and 83%: the sensitivity, specificity, PPV and NPV of GGO were and 43, 84, 40 and 86%, respectively.
Symptom of rhinorrhea and GGO predicted viral pneumonia in patients with CAP. The high specificity of rhinorrhea and GGO suggested that these could be useful indicators for empirical antiviral therapy.
PMCID: PMC4273967  PMID: 25531901
9.  Acid-degradable Core-shell Nanoparticles for Reversed Tamoxifen-resistance in Breast Cancer by Silencing Manganese Superoxide Dismutase (MnSOD) 
Biomaterials  2013;34(38):10228-10237.
Drug resistance acquired by cancer cells is a significant challenge in the clinic and requires impairing the responsible pathological pathway. Administering chemotherapeutics along with silencing resistance-basis activity using RNA interference (RNAi) is expected to restore the activity of the chemotherapeutic. generate synergistic cancer eradication. This study attempted to reverse tamoxifen (TAM)-resistance in breast cancer by silencing a mitochondrial enzyme, manganese superoxide dismutase (MnSOD), which dismutates TAM-induced reactive oxygen species (ROS) (i.e., superoxide) to less harmful hydrogen peroxide and hampers therapeutic effects. Breast cancer cells were co-treated with TAM and MnSOD siRNA-delivering nanoparticles (NPs) made of a siRNA/poly(amidoamine) (PAMAM) dendriplex core and an acid-degradable polyketal (PK) shell. The (siRNA/PAMAM)-PK NPs were designed for the PK shell to shield siRNA from nucleases, minimize detrimental aggregation in serum, and facilitate cytosolic release of siRNA from endosomal compartments. This method of forming the PK shell around the siRNA/PAMAM core via surface-initiated photo-polymerization enables ease of tuning NPs’ size for readily controlled siRNA release kinetics. The resulting NPs were notably homogenous in size, resistant to aggregation in serum, and invulnerable to heparan sulfate-mediated disassembly, compared to siRNA/PAMAM dendriplexes. Gel electrophoresis and confocal microscopy confirmed efficient siRNA release from the (siRNA/PAMAM)-PK NPs upon stimuli-responsive hydrolysis of the PK shell. Sensitization of TAM-resistant MCF7-BK-TR breast cancer cells with (MnSOD siRNA/PAMAM)-PK NPs restored TAM-induced cellular apoptosis in vitro and significantly suppressed tumor growth in vivo, as confirmed by biochemical assays and histological observations. This study implies that combined gene silencing and chemotherapy is a promising strategy to overcoming a significant challenge in cancer therapy.
PMCID: PMC3989112  PMID: 24055523
RNA interference; drug-resistant tumor model; apoptosis; gene therapy; stimuli-responsive nanoparticles
10.  Glioma Cell Growth Inhibition Following Photochemical Internalization Enhanced Non-Viral PTEN Gene Transfection 
Lasers in surgery and medicine  2012;44(9):746-754.
Background and Objective
One of many limitations for cancer gene therapy is the inability of the therapeutic gene to transfect a sufficient number of tumor cells. Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. The utility of PCI for the delivery of the GFP reporter gene on the same plasmid as a tumor suppressor gene (PTEN) was investigated in monolayers of U251 human glioma cells and muticell U87 glioma spheroids.
Materials and Methods
U251 monolayers or U87 spheroids were incubated in AlPcS2a and non-viral vector polyplexes for 18 hours. In all cases, light treatment was performed with a diode laser at a wavelength of 670 nm. The non-viral transfection agents, branched polyethylenimine (bPEI), or protamine sulfate (PS), were used with the plasmid constructs GFP/PTEN or GFP.
PS/GFP polyplexes were much less toxic to the glioma cells compared to bPEI/GFP polyplexes but were highly inefficient at gene transfection if used alone. PCI resulted in a 5- to 10-fold increase in GFP protein expression compared to controls. PCI-bPEI/PTEN or PCI-PS/PTEN transfection of either U251 monolayers or U87 spheroids significantly inhibited their growth. but had no effect on MCF-7 cells containing a wild-type PTEN gene. In addition PCI-GFP transfection of gliomas cells had no effect on their growth pattern.
Collectively, the results suggest that AlPcS2a-mediated PCI can be used to enhance cell growth inhibition via transfection of tumor suppressor genes in glioma cells containing mutant PTEN genes.
PMCID: PMC4141883  PMID: 23018764
glioma; GBM; gene therapy; PDT; PCI; PTEN; photochemical internalization
11.  Update on the Epidemiology, Treatment, and Outcomes of Carbapenem-resistant Acinetobacter infections 
Chonnam Medical Journal  2014;50(2):37-44.
Carbapenem-resistant Acinetobacter species are increasingly recognized as major nosocomial pathogens, especially in patients with critical illnesses or in intensive care. The ability of these organisms to accumulate diverse mechanisms of resistance limits the available therapeutic agents, makes the infection difficult to treat, and is associated with a greater risk of death. In this review, we provide an update on the epidemiology, resistance mechanisms, infection control measures, treatment, and outcomes of carbapenem-resistant Acinetobacter infections.
PMCID: PMC4161759  PMID: 25229014
Acinetobacter baumannii; Colistin; Drug therapy
12.  Are glucocorticoid-induced osteoporosis recommendations sufficient to determine antiosteoporotic treatment for patients with rheumatoid arthritis? 
We investigated differences in identifying candidates for antiosteoporotic treatment in rheumatoid arthritis (RA) patients according to two available clinical guidelines.
We prospectively enrolled 100 female patients aged 50 years or older with RA who visited Hanyang University Hospital for periodic examinations between April 2011 and August 2011. We applied the glucocorticoid-induced osteoporosis (GIOP) recommendations and the National Osteoporosis Foundation (NOF) guidelines to RA patients and examined agreement between the guidelines for identifying candidates for antiosteoporotic treatment. We also analyzed the impact of screening vertebral fractures (VFs) in determining the treatment of osteoporosis in RA patients.
The 57 patients taking glucocorticoids were classified into high-risk (n = 23), medium-risk (n = 16), and low-risk (n = 18) groups according to the GIOP recommendations. Based on the NOF guidelines, 36 of 57 patients were candidates for antiosteoporotic treatment and the agreement between two guidelines was high (κ = 0.76). Two of the 18 patients in the low-risk group and 19 of 43 patients not eligible per the GIOP recommendations were classified as candidates for antiosteoporotic treatment by the NOF guidelines.
In determining antiosteoporotic treatment for RA patients, using only the GIOP recommendations is insufficient. Application of the NOF guidelines in patients not eligible for or classified into the low-risk group per the GIOP recommendations and screening for VFs may be helpful in deciding on antiosteoporotic treatment in RA patients.
PMCID: PMC4101598  PMID: 25045299
Glucocorticoids; Osteoporosis; Arthritis, rheumatoid; Guideline
13.  The Influence of Vertebral Fracture on the Functional Disability of Patients with Rheumatoid Arthritis 
Journal of Korean Medical Science  2014;29(6):859-863.
The aim of the present study was to identify the influence of vertebral fracture (VF) on the functional disability in patients with rheumatoid arthritis (RA). This study consecutively enrolled 100 female patients aged 50 yr or older with RA. All participants underwent lateral imaging of the thoracolumbar spine by simple radiography to identify any VFs. They also completed questionnaires via interview regarding demographics, medical history, and disease outcomes including functional disability. We used univariate analysis to evaluate associations between functional disability and VF, and made multivariate logistic regression models to test independent effect of the presence of VF, the number of VFs, and the severity of VF on functional disability. Among the 100 RA patients, 47 had at least one VF, but 34 of them were asymptomatic that they had experienced a fracture. The multiple VFs ≥ 3 (OR, 8.95; 95% CI, 1.77-44.15, P = 0.01) and moderate or severe VF (OR, 3.38; 95% CI, 1.26-9.04, P = 0.02) were related to disability in univariate analysis. The multiple VFs ≥ 3 (OR, 6.13; 95% CI, 1.02-36.94, P = 0.048) was associated with functional disability of RA patients after adjusting various confounders and it was mainly in walking and arising. The VF might be an important factor which affects functional disability in RA patients.
Graphical Abstract
PMCID: PMC4055822  PMID: 24932090
Arthritis, Rheumatoid; Spinal Fractures; Health Assessment Questionaire
14.  Pheochromocytoma as a Rare Hidden Cause of Inverted Stress Cardiomyopathy 
Stress cardiomyopathy (SCMP) is characterized by a transient left ventricular dysfunction associated with apical ballooning and compensatory hyperkinesias of the basal segments after emotional or physical stress, but inverted or mid-ventricular variants of SCMP have also been described. Although catecholamine excess has been suggested as a possible pathophysiologic mechanism of SCMP, the etiology of SCMP is still unknown. Here, we report a case of inverted type of SCMP with clinical presentation mimicking acute coronary syndromes. The cause or precipitating stressor was unclear initially, but pheochromocytoma has been demonstrated as a cause of SCMP during clinical follow-up at out-patient clinic in the present case. Catecholamine-producing tumors should be included in the evaluation or management of SCMP, even though initial clinical manifestations are not suggestive for pheochromocytoma.
PMCID: PMC4096669  PMID: 25031798
Cardiomyopathy; Stress; Pheochromocytoma
15.  The Role of Bone Scintigraphy in the Diagnosis of Rheumatoid Arthritis According to the 2010 ACR/EULAR Classification Criteria 
Journal of Korean Medical Science  2014;29(2):204-209.
We aimed to investigate the role of bone scintigraphy (BS) in the diagnosis of rheumatoid arthritis (RA) as a supplement to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria. A total of 156 patients who underwent BS with screening laboratory to confirm RA were enrolled. We divided them into two groups according to the presence of arthritis upon the first physical examination, and evaluated the diagnostic validity of BS as an independent (BS only) or assistant diagnostic tool using the 2010 criteria (BS-assisted). Seventy-five patients had active arthritis (Group I), while the remaining 81 patients did not (Group II). Among them, 56 patients in group I and 5 patients in group II were finally classified as RA. In the group I patients who were eligible for application of the 2010 criteria, the sensitivity of the BS only and BS-assisted diagnosis was not superior to that of the 2010 criteria. However, BS-assisted diagnosis showed high positive prediction values in group I patients with 2010 criteria score < 6 and group II patients. Therefore, BS is still helpful to detect RA even after the introduction of the 2010 criteria, especially among patients who do not satisfy the 2010 criteria as well as those who are ineligible for the 2010 criteria due to dubitable arthritis at clinical presentation.
Graphical Abstract
PMCID: PMC3923998  PMID: 24550646
Arthritis, Rheumatoid; 2010 ACR/EULAR Classification Criteria; Bone Scintigraphy
16.  A Case of Endobronchial Aspergilloma Associated with Foreign Body in Immunocompetent Patient without Underlying Lung Disease 
Aspergillus causes a variety of clinical syndromes in the lung including tracheobronchial aspergillosis, invasive aspergillosis, chronic necrotizing pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, and aspergilloma. Aspergilloma usually results from ingrowths of colonized Aspergillus in damaged bronchial tree, pulmonary cyst or cavities of patients with underlying lung diseases. There are a few reports on endobronchial aspergilloma without underlying pulmonary lesion. We have experienced a case of endobronchial aspergilloma associated with foreign body developed in an immunocompetent patient without underlying lung diseases. A 59-year-old man is being hospitalized with recurring hemoptysis for 5 months. X-ray and computed tomography scans of chest showed a nodular opacity in superior segment of left lower lobe. Fiberoptic bronchoscopy revealed an irregular, mass-like, brownish material which totally obstructed the sub-segmental bronchus and a foreign body in superior segmental bronchus of the lower left lobe. Histopathologic examinations of biopsy specimen revealed fungal hyphae, characteristic of Aspergillus species.
PMCID: PMC3672416  PMID: 23750172
Aspergillosis; Foreign Bodies; Immunocompetence
17.  Association of a functional IRF7 variant with systemic lupus erythematosus 
Arthritis and Rheumatism  2011;63(3):749-754.
Previous genome wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 SNP 23kb telomeric to IRF7, in strong association with SLE. This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE.
We genotyped one KIAA1542 SNP rs4963128 and one IRF7 SNP rs1131665 (Q412R) in an Asian population (cases vs. controls: 1302 vs.1479) to assess their association with SLE using custom-designed Beadstation Infinium II platform (Illumina). Subsequently, rs1131665 was further genotyped in independent panels of Chinese (528 vs.527), European American (EA) (446 vs.461) and African American (AA) (159 vs.115) by Taqman genotyping assay to seek confirmation of association in various ethnic groups. Luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF7.
Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, EA and AA populations (case vs. control: 2435 vs. 2582; Pmeta = 6.18×10−6, OR = 1.42[1.22–1.65]). Expression of IRF7 412Q risk allele resulted in a 2-fold increase in ISRE transcriptional activity compared with expression of IRF7 412R (P = 0.0003), suggesting IRF7 412Q confers elevated IRF7 activity and may therefore affect downstream IFN pathway.
We showed that the major allele of a nonsynonymous SNP rs1131665 (412Q) in IRF7 confers elevated IRF7 activation and predisposes to the development of SLE in multiple ethnic groups. This result provides direct genetic evidence supporting IRF7 may be a risk gene for human SLE.
PMCID: PMC3063317  PMID: 21360504
18.  Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility 
PLoS Genetics  2011;7(5):e1002079.
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10−8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10−7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10−7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10−4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.
Author Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing CFH and CFHRs with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of CFHR3 and CFHR1 genes but not previously identified disease-associated exonic variants of CFH. This study provides the first evidence for consistent association between CFH/CFHRs and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.
PMCID: PMC3102741  PMID: 21637784
19.  The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 × 10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.
PMCID: PMC2914299  PMID: 20706608
20.  Genetic Associations of LYN with Systemic Lupus Erythematosus 
Genes and immunity  2009;10(5):397-403.
We targeted LYN, a src-tyosine kinase involved in B cell activation, in case-control association studies using populations of European American, African American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, demonstrates significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (p=1.1 × 10−4, OR=0.81 (95% CI: 0.73 – 0.90)). This SNP is located in the 5′ UTR within the first intron near the transcription initiation site of LYN. Additional SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for SLE susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European American female cases by ACR classification criteria reveals a reduction in the risk of hematologic disorder with rs6983130 compared to cases without hematologic disorders (p=1.5 × 10−3, OR=0.75 (95% C.I.=0.62-0.89)). None of the 90 SNPs tested demonstrate significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.
PMCID: PMC2750001  PMID: 19369946
systemic lupus erythematosus; association; LYN; SNP

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