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Systemic Lupus Erythematosus: HELP
Articles by John B. Harley
Based on 141 articles published since 2008
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Between 2008 and 2019, J. B. Harley wrote the following 141 articles about Lupus Erythematosus, Systemic.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Editorial Everyone comes from somewhere: systemic lupus erythematosus and Epstein-Barr virus induction of host interferon and humoral anti-Epstein-Barr nuclear antigen 1 immunity. 2010

Harley, John B / James, Judith A. · ·Arthritis Rheum · Pubmed #20178135.

ABSTRACT: -- No abstract --

2 Review Genetic susceptibility to lupus: the biological basis of genetic risk found in B cell signaling pathways. 2012

Vaughn, Samuel E / Kottyan, Leah C / Munroe, Melissa E / Harley, John B. ·Cincinnati Children’s Hosptial Medical Center, Cincinnati, OH 45229-3039, USA. ·J Leukoc Biol · Pubmed #22753952.

ABSTRACT: Over 50 genetic variants have been statistically associated with the development of SLE (or lupus). Each genetic association is a key component of a pathway to lupus pathogenesis, the majority of which requires further mechanistic studies to understand the functional changes to cellular physiology. Whereas their use in clinical practice has yet to be established, these genes guide efforts to develop more specific therapeutic approaches. The BCR signaling pathways are rich in lupus susceptibility genes and may well provide novel opportunities for the understanding and clinical treatment of this complex disease.

3 Review The genetics of systemic lupus erythematosus and implications for targeted therapy. 2011

Sestak, Andrea L / Fürnrohr, Barbara G / Harley, John B / Merrill, Joan T / Namjou, Bahram. ·Rheumatology Division, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Andrea-sestak@ouhsc.edu ·Ann Rheum Dis · Pubmed #21339217.

ABSTRACT: Observations of familial aggregation (λs=8-29) and a 40% identical twin concordance rate prompted recent work towards a comprehensive genetic analysis of systemic lupus erythematosus (SLE). Since 2007, the number of genetic effects known to be associated with human lupus has increased by fivefold, underscoring the complexity of inheritance that probably contributes to this disease. Approximately 35 genes associated with lupus have either been replicated in multiple samples or are near the threshold for genome-wide significance (p > 5 x 10⁻⁸). Some are rare variants that convincingly contribute to lupus only in specific subgroups. Strong associations have been found with a large haplotype block in the human leucocyte antigen region, with Fcγ receptors, and with genes coding for complement components, in which a single gene deletion may cause SLE in rare familial cases and copy number variation is more common in the larger population of SLE patients. Examples of newly discovered genes include ITGAM, STAT4 and MECP2/IRAK1. Ongoing studies to build models in which combinations of associated genes might contribute to specific disease manifestations should contribute to improved understanding of disease pathology. In addition, pharmacogenomic components of ongoing clinical trials are likely to provide insights into fundamental disease pathology as well as contributing to informed patient selection for targeted treatments and biomarkers to guide dosing and gauge responsiveness. Besides these potentially valuable new insights into the pathophysiology of an enigmatic, potentially deadly, and, as yet, unsolved disease, genetic studies are likely to suggest novel molecular targets for strategic development of safer and more effective therapeutics.

4 Review Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. 2009

Sawalha, Amr H / Harley, John B / Scofield, R Hal. ·Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. ·J Autoimmun · Pubmed #19464849.

ABSTRACT: Similar to other autoimmune diseases, systemic lupus erythematosus (SLE) predominately affects women. Recent reports demonstrate excess Klinefelter's among men with SLE and a possible under-representation of Turner's syndrome among women with SLE as well as a case report of a 46,XX boy with SLE. These data suggest that risk of SLE is related to a gene dose effect for the X chromosome. Such an effect could be mediated by abnormal inactivation of genes on the X chromosome as has been demonstrated for CD40L, or by genetic polymorphism as has been demonstrated for Xq28. On the other hand, a gene dose effect could also be mediated by a gene without an SLE-associated polymorphism in that a gene that avoids X inactivation will have a higher level of expression in persons with two X chromosomes.

5 Review Recent insights into the genetic basis of systemic lupus erythematosus. 2009

Moser, K L / Kelly, J A / Lessard, C J / Harley, J B. ·Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. moserk@omrf.org ·Genes Immun · Pubmed #19440199.

ABSTRACT: Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.

6 Review Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. 2009

Harley, Isaac T W / Kaufman, Kenneth M / Langefeld, Carl D / Harley, John B / Kelly, Jennifer A. ·Oklahoma Medical Research Foundation, 825 North East 13th Street, Oklahoma City, Oklahoma 73104, USA. ·Nat Rev Genet · Pubmed #19337289.

ABSTRACT: Genome-wide association studies and fine mapping of candidate regions have rapidly advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE). More than 20 robust associations have now been identified and confirmed, providing insights at the molecular level that refine our understanding of the involvement of host immune response processes. In addition, genes with unknown roles in SLE pathophysiology have been identified. These findings may provide new routes towards improved clinical management of this complex disease.

7 Article Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. 2018

Hanscombe, Ken B / Morris, David L / Noble, Janelle A / Dilthey, Alexander T / Tombleson, Philip / Kaufman, Kenneth M / Comeau, Mary / Langefeld, Carl D / Alarcon-Riquelme, Marta E / Gaffney, Patrick M / Jacob, Chaim O / Sivils, Kathy L / Tsao, Betty P / Alarcon, Graciela S / Brown, Elizabeth E / Croker, Jennifer / Edberg, Jeff / Gilkeson, Gary / James, Judith A / Kamen, Diane L / Kelly, Jennifer A / McCune, Joseph / Merrill, Joan T / Petri, Michelle / Ramsey-Goldman, Rosalind / Reveille, John D / Salmon, Jane E / Scofield, Hal / Utset, Tammy / Wallace, Daniel J / Weisman, Michael H / Kimberly, Robert P / Harley, John B / Lewis, Cathryn M / Criswell, Lindsey A / Vyse, Timothy J. ·Department of Medical and Molecular Genetics, King's College London, London, UK. · CHORI, Children's Hospital Oakland Research Institute, Oakland, California, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, UK. · Center for Autoimmune Genomics and Etiology (CAGE), Department of Pediatrics, Cincinnati Children's Medical Center & University of Cincinnati and the US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA. · Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain. · Unit of Chronic Inflammation, Institute of Environmental Medicine, Karolinska Institute, Sweden. · Arthritis & Clinical Immunology Research Program, Division of Genomics and Data Sciences, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. · Keck School of Medicine of USC, Los Angeles, CA, USA. · Department of Medicine, Medical University of South Carolina, Charleston, SC, USA. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA. · Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. · Center for Clinical and Translational Science, University of Alabama at Birmingham, Birmingham, AL, USA. · Division of Rheumatology, Medical University of South Carolina, Charleston, SC, USA. · Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, CA, USA. · Michigan Medicine Rheumatology Clinic,Taubman Center Floor 3 Reception A, 1500 E Medical Center Dr SPC 5358, Ann Arbor, MI, USA. · Oklahoma Medical Research Foundation,825 N.E. 13th Street, Oklahoma City, OK, USA. · Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Feinberg School of Medicine,McGaw Pavilion Suite M-300, 240 E Huron, Chicago, IL, USA. · Department of Internal Medicine, The University of Texas, Fannin, MSB, Houston, TX, USA. · Division of Rheumatology, Hospital for Special Surgery-Weill Cornell Medicine, New York, NY, USA. · Oklahoma Clinical and Translational Science Institute,University of Oklahoma Health Sciences Center, 920 NE Stanton L. Young, Oklahoma City, OK, USA. · University of Chicago Pritzker School of Medicine, Chicago, IL, USA. · MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. · Rosalind Russell / Ephraim P Engleman Rheumatology Research Center, Division of Rheumatology, UCSF School of Medicine, San Francisco, CA, USA. ·Hum Mol Genet · Pubmed #30085094.

ABSTRACT: Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

8 Article Less than 7 hours of sleep per night is associated with transitioning to systemic lupus erythematosus. 2018

Young, K A / Munroe, M E / Harley, J B / Guthridge, J M / Kamen, D L / Gilkensen, G S / Weisman, M H / Karp, D R / Wallace, D J / James, J A / Norris, J M. ·1 Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, USA. · 2 Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, USA. · 3 Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, USA. · 4 US Department of Veterans Affairs Medical Center, Cincinnati, USA. · 5 Division of Rheumatology, Medical University of South Carolina, Charleston, USA. · 6 Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, USA. · 7 Division of Rheumatic Diseases, University of Texas Southwestern Dallas, USA. · 8 Departments of Medicine and Pathology, Oklahoma University Health Sciences Center, Oklahoma City, USA. ·Lupus · Pubmed #29804502.

ABSTRACT: Background The role of sleep in the etiology of systemic lupus erythematosus (SLE) has not been well studied. We examined whether sleep duration was associated with subsequent transitioning to SLE in individuals at risk for SLE. Methods Four hundred and thirty-six relatives of SLE patients who did not have SLE themselves at baseline were evaluated again an average of 6.3 (± 3.9) years later. Fifty-six individuals transitioned to SLE (≥ 4 cumulative American College of Rheumatology (ACR) criteria). Sleep duration, medication use and medical history were assessed by questionnaire; ACR criteria were confirmed by medical record review. Vitamin D was measured by ELISA. Generalized estimating equations, accounting for correlation within families, assessed associations between baseline sleep and the outcome of transitioning to SLE. Results Reporting sleeping less than 7 hours per night at baseline was more common in those who subsequently transitioned than those who did not transition to SLE (55% versus 32%, p = 0.0005; OR: 2.8, 95% CI 1.6-4.9). Those who transitioned to SLE were more likely to sleep less than 7 hours per night than those who did not transition to SLE adjusting for age, sex and race (OR: 2.8, 95% CI 1.6-5.1). This association remained after individual adjustment for conditions and early symptoms that could affect sleep, including prednisone use, vitamin D deficiency and number of ACR criteria (OR: 2.0, 95% CI 1.1-4.2). Conclusion Lack of sleep may be associated with transitioning to SLE, independent of early clinical manifestations of SLE that may influence sleep duration. Further evaluation of sleeping patterns and biomarkers in at-risk individuals is warranted.

9 Article Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. 2018

Harley, John B / Chen, Xiaoting / Pujato, Mario / Miller, Daniel / Maddox, Avery / Forney, Carmy / Magnusen, Albert F / Lynch, Arthur / Chetal, Kashish / Yukawa, Masashi / Barski, Artem / Salomonis, Nathan / Kaufman, Kenneth M / Kottyan, Leah C / Weirauch, Matthew T. ·Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. john.harley@cchmc.org. · Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. john.harley@cchmc.org. · Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. john.harley@cchmc.org. · Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. john.harley@cchmc.org. · US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA. john.harley@cchmc.org. · Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. · Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. · Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. · Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. · Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. · US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA. · Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. leah.kottyan@cchmc.org. · Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. leah.kottyan@cchmc.org. · Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. matthew.weirauch@cchmc.org. · Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. matthew.weirauch@cchmc.org. · Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. matthew.weirauch@cchmc.org. · Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. matthew.weirauch@cchmc.org. ·Nat Genet · Pubmed #29662164.

ABSTRACT: Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. Using new computational methods, we show that transcription factors (TFs) occupy multiple loci associated with individual complex genetic disorders. Application to 213 phenotypes and 1,544 TF binding datasets identified 2,264 relationships between hundreds of TFs and 94 phenotypes, including androgen receptor in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and many coclustering human TFs, showing gene-environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent on EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new models for disease origins.

10 Article Characterization and classification of lupus patients based on plasma thermograms. 2017

Garbett, Nichola C / Brock, Guy N / Chaires, Jonathan B / Mekmaysy, Chongkham S / DeLeeuw, Lynn / Sivils, Kathy L / Harley, John B / Rovin, Brad H / Kulasekera, K B / Jarjour, Wael N. ·James Graham Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, United States of America. · Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, United States of America. · Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America. · U.S. Department of Veterans Affairs Medical Center, Cincinnati, OH, United States of America. · The Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center & University of Cincinnati, Cincinnati, OH, United States of America. · Nephrology Division, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America. · Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America. ·PLoS One · Pubmed #29149219.

ABSTRACT: OBJECTIVE: Plasma thermograms (thermal stability profiles of blood plasma) are being utilized as a new diagnostic approach for clinical assessment. In this study, we investigated the ability of plasma thermograms to classify systemic lupus erythematosus (SLE) patients versus non SLE controls using a sample of 300 SLE and 300 control subjects from the Lupus Family Registry and Repository. Additionally, we evaluated the heterogeneity of thermograms along age, sex, ethnicity, concurrent health conditions and SLE diagnostic criteria. METHODS: Thermograms were visualized graphically for important differences between covariates and summarized using various measures. A modified linear discriminant analysis was used to segregate SLE versus control subjects on the basis of the thermograms. Classification accuracy was measured based on multiple training/test splits of the data and compared to classification based on SLE serological markers. RESULTS: Median sensitivity, specificity, and overall accuracy based on classification using plasma thermograms was 86%, 83%, and 84% compared to 78%, 95%, and 86% based on a combination of five antibody tests. Combining thermogram and serology information together improved sensitivity from 78% to 86% and overall accuracy from 86% to 89% relative to serology alone. Predictive accuracy of thermograms for distinguishing SLE and osteoarthritis / rheumatoid arthritis patients was comparable. Both gender and anemia significantly interacted with disease status for plasma thermograms (p<0.001), with greater separation between SLE and control thermograms for females relative to males and for patients with anemia relative to patients without anemia. CONCLUSION: Plasma thermograms constitute an additional biomarker which may help improve diagnosis of SLE patients, particularly when coupled with standard diagnostic testing. Differences in thermograms according to patient sex, ethnicity, clinical and environmental factors are important considerations for application of thermograms in a clinical setting.

11 Article T-bet 2017

Liu, Ya / Zhou, Shiyu / Qian, Jie / Wang, Yan / Yu, Xiang / Dai, Dai / Dai, Min / Wu, Lingling / Liao, Zhuojun / Xue, Zhixin / Wang, Jiehua / Hou, Goujun / Ma, Jianyang / Harley, John B / Tang, Yuanjia / Shen, Nan. ·Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shan Dong Middle Road, Shanghai, 200001, China. · Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Chinese Academy of Sciences (CAS), Shanghai, China. · Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, and Cincinnati VA Medical Center, Cincinnati, Ohio, USA. · Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shan Dong Middle Road, Shanghai, 200001, China. nanshensibs@gmail.com. · Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Chinese Academy of Sciences (CAS), Shanghai, China. nanshensibs@gmail.com. · Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. nanshensibs@gmail.com. · State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao tong University School of Medicine, Shanghai, China. nanshensibs@gmail.com. ·Arthritis Res Ther · Pubmed #28982388.

ABSTRACT: BACKGROUND: A hallmark of systemic lupus erythematosus is high titers of circulating autoantibodies. Recently, a novel CD11c METHODS: cGVHD was induced by an intraperitoneal injection of 5 × 10 RESULTS: The percentage and absolute number of CD11c CONCLUSION: T-bet

12 Article Transancestral mapping and genetic load in systemic lupus erythematosus. 2017

Langefeld, Carl D / Ainsworth, Hannah C / Cunninghame Graham, Deborah S / Kelly, Jennifer A / Comeau, Mary E / Marion, Miranda C / Howard, Timothy D / Ramos, Paula S / Croker, Jennifer A / Morris, David L / Sandling, Johanna K / Almlöf, Jonas Carlsson / Acevedo-Vásquez, Eduardo M / Alarcón, Graciela S / Babini, Alejandra M / Baca, Vicente / Bengtsson, Anders A / Berbotto, Guillermo A / Bijl, Marc / Brown, Elizabeth E / Brunner, Hermine I / Cardiel, Mario H / Catoggio, Luis / Cervera, Ricard / Cucho-Venegas, Jorge M / Dahlqvist, Solbritt Rantapää / D'Alfonso, Sandra / Da Silva, Berta Martins / de la Rúa Figueroa, Iñigo / Doria, Andrea / Edberg, Jeffrey C / Endreffy, Emőke / Esquivel-Valerio, Jorge A / Fortin, Paul R / Freedman, Barry I / Frostegård, Johan / García, Mercedes A / de la Torre, Ignacio García / Gilkeson, Gary S / Gladman, Dafna D / Gunnarsson, Iva / Guthridge, Joel M / Huggins, Jennifer L / James, Judith A / Kallenberg, Cees G M / Kamen, Diane L / Karp, David R / Kaufman, Kenneth M / Kottyan, Leah C / Kovács, László / Laustrup, Helle / Lauwerys, Bernard R / Li, Quan-Zhen / Maradiaga-Ceceña, Marco A / Martín, Javier / McCune, Joseph M / McWilliams, David R / Merrill, Joan T / Miranda, Pedro / Moctezuma, José F / Nath, Swapan K / Niewold, Timothy B / Orozco, Lorena / Ortego-Centeno, Norberto / Petri, Michelle / Pineau, Christian A / Pons-Estel, Bernardo A / Pope, Janet / Raj, Prithvi / Ramsey-Goldman, Rosalind / Reveille, John D / Russell, Laurie P / Sabio, José M / Aguilar-Salinas, Carlos A / Scherbarth, Hugo R / Scorza, Raffaella / Seldin, Michael F / Sjöwall, Christopher / Svenungsson, Elisabet / Thompson, Susan D / Toloza, Sergio M A / Truedsson, Lennart / Tusié-Luna, Teresa / Vasconcelos, Carlos / Vilá, Luis M / Wallace, Daniel J / Weisman, Michael H / Wither, Joan E / Bhangale, Tushar / Oksenberg, Jorge R / Rioux, John D / Gregersen, Peter K / Syvänen, Ann-Christine / Rönnblom, Lars / Criswell, Lindsey A / Jacob, Chaim O / Sivils, Kathy L / Tsao, Betty P / Schanberg, Laura E / Behrens, Timothy W / Silverman, Earl D / Alarcón-Riquelme, Marta E / Kimberly, Robert P / Harley, John B / Wakeland, Edward K / Graham, Robert R / Gaffney, Patrick M / Vyse, Timothy J. ·Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA. · Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA. · Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Diseases, King's College London, Guy's Hospital, London SE1 9RT, UK. · Arthritis &Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA. · Center for Human Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA. · Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. · Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA. · Division of Clinical Immunology and Rheumatology, UAB School of Medicine, Birmingham, Alabama 35294, USA. · Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala 752 36, Sweden. · Departamento de Reumatología, Hospital G. Almenara y Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima 15081, Perú. · Hospital Italiano de Córdoba, Córdoba X5004BAL, Argentina. · Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico. · Department of Clinical Sciences, Rheumatology, Lund University, Lund 22362, Sweden. · Hospital Eva Perón, Granadero Baigorria S2152EDD, Argentina. · Department of Internal Medicine and Rheumatology, Martini Hospital, Van Swietenplein 1, 9728, NT, Groningen, The Netherlands. · Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio 45229, USA. · Centro de Investigación Clínica de Morelia, Morelia, Michoacán 58070, Mexico. · Hospital Italiano de Buenos Aires, 1181, Buenos Aires C1181ACH, Argentina. · Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Barcelona, Catalonia 08007, Spain. · Department of Public Health and Clinical Medicine, Division of Rheumatology, Umeå University, Umeå 901 87, Sweden. · Department of Health Sciences and Institute of Research in Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara 28100, Italy. · Unidade Multidisciplinar em Investigação Biomédica/Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto, Porto 4099-003, Portugal. · Department of Rheumatology, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria 35010, Spain. · Division of Rheumatology, Department of Medicine (DIMED), University of Padua, Padua 35122, Italy. · Department of Pediatrics and Child Health Center, Albert Szent-Györgyi Medical Center, Faculty of Medicine, University of Szeged, Szeged H-6720, Hungary. · Hospital Universitario 'Dr José Eleuterio González' Universidad Autonoma de Nuevo León, Monterrey 64020, México. · CHU de Québec Université Laval, Québec, Canada G1R 2JG. · Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA. · Institute of Environmental Medicine, Unit of Immunology and Chronic diseases, Karolinska Institutet, Stockholm 171 77, Sweden. · Division of Rheumatology, Hospital Interzonal General de Agudos General San Martín, La Plata 1900, Argentina. · University of Guadalajara, Departamento de Fisiología, Guadalajara, Jalisco 44100, Mexico. · Centre for Prognosis Studies in The Rheumatic Diseases, Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada. · Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden. · Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. · Department of Rheumatology and Clinical Immunology,University Medical Center Groningen,University of Groningen, Groningen 9713 GZ, The Netherlands. · Department of Immunology, University of Texas SouthWestern Medical Center, Dallas, Texas 75235, USA. · Department of Pediatrics, Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. · Department of Rheumatology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged H-6720, Hungary. · Department of Rheumatology, Odense University Hospital, Odense 5000, Denmark. · Rheumatology, Cliniques Universitaires Saint-Luc &Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium. · Hospital General de Culiacán, Sinaloa 80220, Mexico. · Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada 18100, Spain. · University of Michigan Medical Center, Ann Arbor, Michigan 48103, USA. · Centro de Estudios Reumatológicos, Santiago de Chile, Santiago 7500000, Chile. · Departamento de Reumatología, Hospital General de México, Mexico D.F., Mexico. · Department of Rheumatology, Mayo Clinic, Rochester, Minnesota 94158, USA. · Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, México. · Unidad de Enfermedades Autoimmunes Sistémicas, UGC Medicina Interna, Hospital Universitario San Cecilio, Granada 18007, Spain. · Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21218, USA. · Rheumatology Division, McGill University, Montreal, Quebec H3A 0G4, Canada. · Department of Rheumatology, Sanatorio Parque, Rosario S2000, Argentina. · University of Western Ontario, London, Ontario, Canada M5T 2S8. · Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. · The University of Texas Health Science Center at Houston (UTHealth) Medical School, Houston, Texas 77030, USA. · Hospital Universitario Virgen de las Nieves, Granada 18014, Spain. · Instituto Nacional de Ciencias Médicas y Nutrición, Department of Endocrinology and Metabolism, Vasco de Quiroga 15, Mexico City 14080, Mexico. · Unidad Reumatología y Enfermedades Autoinmunes H.I.G.A. Dr Alende Mar del Plata, Buenos Aires B7600, Argentina. · Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca'Granda Ospedale Ma Repiore Policlinico and University of Milan, Milan 20122, Italy. · Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California 95616, USA. · Rheumatology Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine, Linköping University, Linköping 581 83, Sweden. · Ministry of Health, San Fernando del Valle de Catamarca, Catamarca K4700, Argentina. · Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Lund 221 00, Sweden. · Unidad de Biología Molecular y Medicina Genómica Instituto de Investigaciones Biomédicas/UNAM Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico. · Hospital Santo Antonio, Universidade do Porto, Porto 4099-003, Portugal. · University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico. · Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California 90048, USA. · Human Genetics, Genentech Inc, South San Francisco, California 94080, USA. · Department of Neurology and Institute of Human Genetics, University of California at San Francisco, San Francisco, California 94158, USA. · Université de Montréal and the Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8. · Center for Genomics &Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA. · Department of Medical Sciences, Rheumatology, Uppsala University, 752 36, Sweden. · Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, Division of Rheumatology, UCSF School of Medicine, San Francisco, California 94158, USA. · Keck School of Medicine of USC, Los Angeles, California 90033, USA. · Department of Pediatrics, Duke University, Durham, North Carolina 27708, USA. · Department of Pediatrics and the Institute of Medical Sciences, The Hospital for Sick Children, Hospital for Sick Children Research Institute and University of Toronto, Ontario, Canada M5G 1X8. · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada 18007, Spain. · Unit of Institute of Environmental Medicine, Karolinska Institute, Solnavägen 171 77, Sweden. ·Nat Commun · Pubmed #28714469.

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10

13 Article Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome. 2017

Sharma, Rohan / Harris, Valerie M / Cavett, Joshua / Kurien, Biji T / Liu, Ke / Koelsch, Kristi A / Fayaaz, Anum / Chaudhari, Kaustubh S / Radfar, Lida / Lewis, David / Stone, Donald U / Kaufman, C Erick / Li, Shibo / Segal, Barbara / Wallace, Daniel J / Weisman, Michael H / Venuturupalli, Swamy / Kelly, Jennifer A / Pons-Estel, Bernardo / Jonsson, Roland / Lu, Xianglan / Gottenberg, Jacques-Eric / Anaya, Juan-Manuel / Cunninghame-Graham, Deborah S / Huang, Andrew J W / Brennan, Michael T / Hughes, Pamela / Alevizos, Ilias / Miceli-Richard, Corinne / Keystone, Edward C / Bykerk, Vivian P / Hirschfield, Gideon / Nordmark, Gunnel / Bucher, Sara Magnusson / Eriksson, Per / Omdal, Roald / Rhodus, Nelson L / Rischmueller, Maureen / Rohrer, Michael / Wahren-Herlenius, Marie / Witte, Torsten / Alarcón-Riquelme, Marta / Mariette, Xavier / Lessard, Christopher J / Harley, John B / Ng, Wan-Fai / Rasmussen, Astrid / Sivils, Kathy L / Scofield, R Hal. ·Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, and Department of Veterans Affairs Medical Center, Oklahoma City. · Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City. · Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio. · Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma. · University of Oklahoma Health Sciences Center, Oklahoma City. · Johns Hopkins University, Baltimore, Maryland, and King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. · University of Minnesota Medical School, Minneapolis. · Cedars-Sinai Medical Center, Los Angeles, California. · Oklahoma Medical Research Foundation, Oklahoma City. · Sanatorio Parque, Rosario, Argentina. · University of Bergen and Haukeland University Hospital, Bergen, Norway. · Strasbourg University, Strasbourg, France. · Universidad del Rosario, Bogota, Colombia. · King's College London, London, UK. · University of Minnesota, Minneapolis. · Carolinas Medical Center, Charlotte, North Carolina. · National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD. · Department of Rheumatology, Université Paris-Sud, AP-HP, INSERM U1012, Le Kremlin-Bicêtre, France. · Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada. · Hospital for Special Surgery, New York, New York. · University of Birmingham, Birmingham, UK. · Uppsala University, Uppsala, Sweden. · Örebro University Hospital, Örebro, Sweden. · Linköping University, Linköping, Sweden. · Stavanger University Hospital, Stavanger, Norway. · The Queen Elizabeth Hospital, Woodville South, and University of Adelaide, Adelaide, South Australia, Australia. · Karolinska Institutet, Stockholm, Sweden. · Hannover Medical School, Hannover, Germany. · Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain, and Karolinska Institutet, Stockholm, Sweden. · Cincinnati Children's Hospital Medical Center, University of Cincinnati, and Ohio Department of Veterans Affairs Medical Center, Cincinnati. · Newcastle University, Newcastle upon Tyne, UK. ·Arthritis Rheumatol · Pubmed #28692793.

ABSTRACT: OBJECTIVE: Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of ~10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. METHODS: We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients. RESULTS: Among ~2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among ~2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in ~1 in 25,000-50,000 live female births, while partial triplications are even rarer. CONCLUSION: Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.

14 Article Clinical and Serologic Features in Patients With Incomplete Lupus Classification Versus Systemic Lupus Erythematosus Patients and Controls. 2017

Aberle, Teresa / Bourn, Rebecka L / Munroe, Melissa E / Chen, Hua / Roberts, Virginia C / Guthridge, Joel M / Bean, Krista / Robertson, Julie M / Sivils, Kathy L / Rasmussen, Astrid / Liles, Meghan / Merrill, Joan T / Harley, John B / Olsen, Nancy J / Karp, David R / James, Judith A. ·Oklahoma Medical Research Foundation, Oklahoma City. · Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio. · Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania. · University of Texas Southwestern Medical Center, Dallas. · Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City. ·Arthritis Care Res (Hoboken) · Pubmed #28118528.

ABSTRACT: OBJECTIVE: Incomplete lupus erythematosus (ILE) involves clinical and/or serologic manifestations consistent with but insufficient for systemic lupus erythematosus (SLE) classification. Because the nature of ILE is poorly understood and no treatment recommendations exist, we examined the clinical manifestations, medication history, and immunologic features in a diverse collection of ILE and SLE patients. METHODS: Medical records of subjects enrolled in the Lupus Family Registry and Repository were reviewed for medication history and American College of Rheumatology (ACR) classification criteria to identify ILE patients (3 ACR criteria; n = 440) and SLE patients (≥4 ACR criteria; n = 3,397). Participants completed the Connective Tissue Disease Screening Questionnaire. Anticardiolipin and plasma B lymphocyte stimulator (BLyS) were measured by enzyme-linked immunosorbent assay, antinuclear antibodies (ANAs) by indirect immunofluorescence, and 13 autoantibodies by bead-based assays. RESULTS: On average, ILE patients were older than SLE patients (46.2 years versus 42.0 years; P < 0.0001), and fewer ILE patients were African American (23.9% versus 32.2%; P < 0.001). ILE patients exhibited fewer autoantibody specificities than SLE patients (1.3 versus 2.6; P < 0.0001) and were less likely to have ANA titers ≥1:1,080 (10.5% versus 19.5%; P < 0.0001). BLyS levels were intermediate in ILE patients (controls < ILE; P = 0.016; ILE < SLE; P = 0.008). Pericarditis, renal, or neurologic manifestations occurred in 12.5% of ILE patients and were associated with non-European American race/ethnicity (P = 0.012). Hydroxychloroquine use increased over time, but was less frequent in ILE than SLE patients (65.2% versus 83.1%; P < 0.0001). CONCLUSION: Although usually characterized by milder symptoms, ILE manifestations may require immunomodulatory treatments. Longitudinal studies are necessary to understand how ILE affects organ damage and future SLE risk, and to delineate molecular pathways unique to ILE.

15 Article Discerning Risk of Disease Transition in Relatives of Systemic Lupus Erythematosus Patients Utilizing Soluble Mediators and Clinical Features. 2017

Munroe, Melissa E / Young, Kendra A / Kamen, Diane L / Guthridge, Joel M / Niewold, Timothy B / Costenbader, Karen H / Weisman, Michael H / Ishimori, Mariko L / Wallace, Daniel J / Gilkeson, Gary S / Karp, David R / Harley, John B / Norris, Jill M / James, Judith A. ·Oklahoma Medical Research Foundation, Oklahoma City. · Colorado School of Public Health, Aurora. · Medical University of South Carolina, Charleston. · Mayo Clinic, Rochester, Minnesota. · Brigham and Women's Hospital, Boston, Massachusetts. · Cedars-Sinai Medical Center, Los Angeles, California. · University of Texas Southwestern Medical Center, Dallas. · Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio. · Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City. ·Arthritis Rheumatol · Pubmed #27863174.

ABSTRACT: OBJECTIVE: Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential for curtailing irreversible inflammatory damage. The aim of this study was to identify factors associated with transition to classified disease that would inform our understanding of the risk of SLE. METHODS: Previously identified blood relatives of patients with SLE, who had <4 American College of Rheumatology (ACR) classification criteria for SLE at baseline, were enrolled in this follow-up study (n = 409 unaffected relatives). Participants provided detailed family, demographic, and clinical information, including the SLE-specific portion of the Connective Tissue Disease Screening Questionnaire (SLE-CSQ). Serum and plasma samples were tested for the presence of lupus-associated autoantibodies and 52 soluble mediators. Generalized estimating equations (GEEs) were applied to identify factors predictive of disease transition. RESULTS: Of the 409 unaffected relatives of SLE patients, 45 (11%) had transitioned to classified SLE at follow-up (mean time to follow-up 6.4 years). Relatives who transitioned to SLE displayed more lupus-associated autoantibody specificities and higher SLE-CSQ scores (P < 0.0001) at baseline than did relatives who did not transition. Importantly, those who had developed SLE during the follow-up period also had elevated baseline plasma levels of inflammatory mediators, including B lymphocyte stimulator, stem cell factor (SCF), and interferon-associated chemokines (P ≤ 0.02), with concurrent decreases in the levels of regulatory mediators, transforming growth factor β (TGFβ), and interleukin-10 (P ≤ 0.03). GEE analyses revealed that baseline SLE-CSQ scores or ACR scores (number of ACR criteria satisfied) and plasma levels of SCF and TGFβ, but not autoantibodies, were significant and independent predictors of SLE transition (P ≤ 0.03). CONCLUSION: Preclinical alterations in levels of soluble mediators may predict transition to classified disease in relatives of SLE patients. Thus, immune perturbations precede SLE classification and can help identify high-risk relatives for rheumatology referral and potential enrollment in prevention trials.

16 Article Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus. 2017

Young, Kendra A / Munroe, Melissa E / Guthridge, Joel M / Kamen, Diane L / Niewold, Timothy B / Gilkeson, Gary S / Weisman, Michael H / Ishimori, Mariko L / Kelly, Jennifer / Gaffney, Patrick M / Sivils, Kathy H / Lu, Rufei / Wallace, Daniel J / Karp, David R / Harley, John B / James, Judith A / Norris, Jill M. ·Colorado School of Public Health, Aurora, Colorado, USA. · Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. · Medical University of South Carolina, Charleston, South Carolina, USA. · Mayo Clinic, Rochester, Minnesota, USA. · Cedars-Sinai Medical Center, Los Angeles, California, USA. · Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, USA. · University of Texas Southwestern Medical Center, Dallas, Texas, USA. · Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. · US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. ·Ann Rheum Dis · Pubmed #27283331.

ABSTRACT: OBJECTIVE: We examined whether measures of vitamin D were associated with transitioning to systemic lupus erythematosus (SLE) in individuals at risk for SLE. METHODS: 436 individuals who reported having a relative with SLE but who did not have SLE themselves were evaluated at baseline and again an average of 6.3 (±3.9) years later. Fifty-six individuals transitioned to SLE (≥4 cumulative American College of Rheumatology criteria). 25-Hydroxyvitamin D (25[OH]D) levels were measured by ELISA. Six single-nucleotide polymorphisms in four vitamin D genes were genotyped. Generalised estimating equations, adjusting for correlation within families, were used to test associations between the vitamin D variables and the outcome of transitioning to SLE. RESULTS: Mean baseline 25[OH]D levels (p=0.42) and vitamin D supplementation (p=0.65) were not different between those who did and did not transition to SLE. Vitamin D deficiency (25[OH]D <20 ng/mL) was greater in those who transitioned compared with those who did not transition to SLE (46% vs 33%, p=0.05). The association between 25[OH]D and SLE was modified by CYP24A1 rs4809959, where for each additional minor allele increased 25[OH]D was associated with decreased SLE risk: zero minor alleles (adjusted OR: 1.03, CI 0.98 to 1.09), one minor allele (adjusted OR: 1.01, CI 0.97 to 1.05) and two minor alleles (adjusted OR: 0.91, CI 0.84 to 0.98). Similarly, vitamin D deficiency significantly increased the risk of transitioning to SLE in those with two minor alleles at rs4809959 (adjusted OR: 4.90, CI 1.33 to 18.04). CONCLUSIONS: Vitamin D status and CYP24A1 may have a combined role in the transition to SLE in individuals at increased genetic risk for SLE.

17 Article Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. 2016

Lu, Rufei / Munroe, Melissa E / Guthridge, Joel M / Bean, Krista M / Fife, Dustin A / Chen, Hua / Slight-Webb, Samantha R / Keith, Michael P / Harley, John B / James, Judith A. ·Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104. · Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104. · Rheumatology Service, Walter Reed National Military Medical Center, Bethesda, MD 20889. · Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, OH 45229. ·J Autoimmun · Pubmed #27338520.

ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a poorly understood preclinical stage of immune dysregulation and symptom accrual. Accumulation of antinuclear autoantibody (ANA) specificities is a hallmark of impending clinical disease. Yet, many ANA-positive individuals remain healthy, suggesting that additional immune dysregulation underlies SLE pathogenesis. Indeed, we have recently demonstrated that interferon (IFN) pathways are dysregulated in preclinical SLE. To determine if other forms of immune dysregulation contribute to preclinical SLE pathogenesis, we measured SLE-associated autoantibodies and soluble mediators in samples from 84 individuals collected prior to SLE classification (average timespan = 5.98 years), compared to unaffected, healthy control samples matched by race, gender, age (±5 years), and time of sample procurement. We found that multiple soluble mediators, including interleukin (IL)-5, IL-6, and IFN-γ, were significantly elevated in cases compared to controls more than 3.5 years pre-classification, prior to or concurrent with autoantibody positivity. Additional mediators, including innate cytokines, IFN-associated chemokines, and soluble tumor necrosis factor (TNF) superfamily mediators increased longitudinally in cases approaching SLE classification, but not in controls. In particular, levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were comparable in cases and controls until less than 10 months pre-classification. Over the entire pre-classification period, random forest models incorporating ANA and anti-Ro/SSA positivity with levels of IL-5, IL-6, and the IFN-γ-induced chemokine, MIG, distinguished future SLE patients with 92% (±1.8%) accuracy, compared to 78% accuracy utilizing ANA positivity alone. These data suggest that immune dysregulation involving multiple pathways contributes to SLE pathogenesis. Importantly, distinct immunological profiles are predictive for individuals who will develop clinical SLE and may be useful for delineating early pathogenesis, discovering therapeutic targets, and designing prevention trials.

18 Article MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells. 2016

Han, Xiao / Wang, Yan / Zhang, Xiaoyan / Qin, Yuting / Qu, Bo / Wu, Lingling / Ma, Jianyang / Zhou, Zhenyuan / Qian, Jie / Dai, Min / Tang, Yuanjia / Chan, Edward K L / Harley, John B / Zhou, Shiyu / Shen, Nan. ·Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China. · Shanghai Institute of Rheumatology, Renji Hospital, and Shanghai Jiao Tong University School of Medicine, Shanghai, China. · University of Florida, Gainesville. · Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, Ohio. · Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Institute of Rheumatology, Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, and Shanghai Jiao Tong University School of Medicine, Shanghai, China, and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. ·Arthritis Rheumatol · Pubmed #27111096.

ABSTRACT: OBJECTIVE: Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA-130b (miR-130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN. METHODS: Kidney tissues from patients and (NZB × NZW)F1 lupus-prone mice were collected for detecting miR-130b levels. Primary renal mesangial cells (RMCs) were used to determine the role of miR-130b in the IFN pathway. We overexpressed miR-130b by administering miR-130b agomir in a mouse model of IFNα-accelerated LN to test its therapeutic efficacy. RESULTS: Down-regulated miR-130b expression was observed in kidney tissues from patients and lupus-prone mice. Further analysis showed that underexpression of miR-130b correlated negatively with abnormal activation of the IFN response in LN patients. In vitro, overexpressing miR-130b suppressed signaling downstream from the type I IFN pathway in RMCs by targeting IFN regulatory factor 1 (IRF-1). The opposite effect was observed when endogenous miR-130b expression was inhibited. The inverse correlation between IRF1 and miR-130b levels was detected in renal biopsy samples from LN patients. More importantly, in vivo administration of miR-130b agomir reduced IFNα-accelerated progression of LN, with decreased proteinuria, lower levels of immune complex deposition, and lack of glomerular lesions. CONCLUSION: MicroRNA-130b is a novel negative regulator of the type I IFN pathway in renal cells. Overexpression of miR-130b in vivo ameliorates IFNα-accelerated LN, providing potential novel strategies for therapeutic intervention in LN.

19 Article Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome. 2016

Harris, Valerie M / Sharma, Rohan / Cavett, Joshua / Kurien, Biji T / Liu, Ke / Koelsch, Kristi A / Rasmussen, Astrid / Radfar, Lida / Lewis, David / Stone, Donald U / Kaufman, C Erick / Li, Shibo / Segal, Barbara / Wallace, Daniel J / Weisman, Michael H / Venuturupalli, Swamy / Kelly, Jennifer A / Alarcon-Riquelme, Marta E / Pons-Estel, Bernardo / Jonsson, Roland / Lu, Xianglan / Gottenberg, Jacques-Eric / Anaya, Juan-Manuel / Cunninghame-Graham, Deborah S / Huang, Andrew J W / Brennan, Michael T / Hughes, Pamela / Alevizos, Ilias / Miceli-Richard, Corinne / Keystone, Edward C / Bykerk, Vivian P / Hirschfield, Gideon / Xie, Gang / Siminovitch, Katherine A / Ng, Wan-Fai / Nordmark, Gunnel / Bucher, Sara Magnusson / Eriksson, Per / Omdal, Roald / Rhodus, Nelson L / Rischmueller, Maureen / Rohrer, Michael / Wahren-Herlenius, Marie / Witte, Torsten / Mariette, Xavier / Lessard, Christopher J / Harley, John B / Sivils, Kathy L / Scofield, R Hal. ·Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA. · Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA. · Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA. · Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. · Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, USA. · Dean McGee Eye Institute and Department of Ophthalmology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA. · Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. · Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA. · Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Center Pfizer, University of Granada, Andalusian Government for Genomics and Oncological Research, PTS Granada, 18016, Spain. · Sanatorio Parque, Rosario, Argentina. · Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway; Department of Rheumatology, Haukeland University Hospital, Bergen 5021, Norway. · Strasbourg University, Strasbourg, France. · Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia. · Division of Genetics and Molecular Medicine and Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK. · Department of Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA. · Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA. · Molecular Physiology & Therapeutic Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA. · Department of Rheumatology, Université Paris-Sud, AP-HP, INSERM U1012, Le Kremlin-Bicêtre, France. · Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada. · Hospital for Special Surgery, New York, USA. · NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK. · Samuel Lunenfeld and Toronto General Research Institutes, Departments of Medicine, Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. · Musculoskeletal Research Group, Institute of Cellular Medicine & NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK. · Section of Rheumatology, Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Department of Rheumatology, Örebro University Hospital, Örebro, Sweden. · Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway. · Rheumatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. · Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, USA. · Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA 5000, Australia. · Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. · Clinic for Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany. · Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Medical Service, Department of Veterans Affairs Medical Center, Cincinnati, OH, USA. · Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA. Electronic address: hal-scofield@omrf.ouhsc.edu. ·Clin Immunol · Pubmed #27109640.

ABSTRACT: Primary Sjögren's syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelter's syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47,XXY, p=0.0012 by Fisher's exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fisher's exact test p=NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA.

20 Article Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. 2016

Munroe, Melissa E / Lu, Rufei / Zhao, Yan D / Fife, Dustin A / Robertson, Julie M / Guthridge, Joel M / Niewold, Timothy B / Tsokos, George C / Keith, Michael P / Harley, John B / James, Judith A. ·Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. · Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA. · Department of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. · Department of Rheumatology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA. · Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. ·Ann Rheum Dis · Pubmed #27088255.

ABSTRACT: OBJECTIVES: The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE. METHODS: Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (±5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models. RESULTS: In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, macrophage chemoattractant protein (MCP)-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification). CONCLUSIONS: Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.

21 Article Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. 2016

Raj, Prithvi / Rai, Ekta / Song, Ran / Khan, Shaheen / Wakeland, Benjamin E / Viswanathan, Kasthuribai / Arana, Carlos / Liang, Chaoying / Zhang, Bo / Dozmorov, Igor / Carr-Johnson, Ferdicia / Mitrovic, Mitja / Wiley, Graham B / Kelly, Jennifer A / Lauwerys, Bernard R / Olsen, Nancy J / Cotsapas, Chris / Garcia, Christine K / Wise, Carol A / Harley, John B / Nath, Swapan K / James, Judith A / Jacob, Chaim O / Tsao, Betty P / Pasare, Chandrashekhar / Karp, David R / Li, Quan Zhen / Gaffney, Patrick M / Wakeland, Edward K. ·Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States. · School of Biotechnology, Shri Mata Vaishno Devi University, Katra, India. · Department of Neurology, Yale School of Medicine, New Haven, United States. · Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United States. · Pole de pathologies rhumatismales, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Bruxelles, Belgium. · Division of Rheumatology, Department of Medicine, Penn State Medical School, Hershey, United States. · Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States. · Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States. · Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, United States. · Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, United States. · Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States. · Cincinnati VA Medical Center, Cincinnati, United States. · Cincinnati Children's Hospital Medical Center, Cincinnati, United States. · Department of Medicine, University of Southern California, Los Angeles, United States. · Department of Medicine, University of California, Los Angeles, Los Angeles, United States. · Rheumatic Diseases Division, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, United States. ·Elife · Pubmed #26880555.

ABSTRACT: Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.

22 Article High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. 2016

Sun, Celi / Molineros, Julio E / Looger, Loren L / Zhou, Xu-Jie / Kim, Kwangwoo / Okada, Yukinori / Ma, Jianyang / Qi, Yuan-Yuan / Kim-Howard, Xana / Motghare, Prasenjeet / Bhattarai, Krishna / Adler, Adam / Bang, So-Young / Lee, Hye-Soon / Kim, Tae-Hwan / Kang, Young Mo / Suh, Chang-Hee / Chung, Won Tae / Park, Yong-Beom / Choe, Jung-Yoon / Shim, Seung Cheol / Kochi, Yuta / Suzuki, Akari / Kubo, Michiaki / Sumida, Takayuki / Yamamoto, Kazuhiko / Lee, Shin-Seok / Kim, Young Jin / Han, Bok-Ghee / Dozmorov, Mikhail / Kaufman, Kenneth M / Wren, Jonathan D / Harley, John B / Shen, Nan / Chua, Kek Heng / Zhang, Hong / Bae, Sang-Cheol / Nath, Swapan K. ·Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. · Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, USA. · Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China. · Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea. · Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. · Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. · Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. · School of Medicine, Kyungpook National University Hospital, Daegu, Korea. · Department of Rheumatology, Ajou University Hospital, Suwon, Korea. · Department of Internal Medicine, Dong-A University Hospital, Busan, Korea. · Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. · Department of Internal Medicine, Daegu Catholic University Hospital, Daegu, Korea. · Daejeon Rheumatoid and Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Korea. · Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan. · Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. · Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. · Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Rheumatology, Chonnam National University Hospital, Gwangju, Korea. · Korea National Institute of Health, Osong, Korea. · Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA. · Department of Pediatrics, Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. · Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. · Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. ·Nat Genet · Pubmed #26808113.

ABSTRACT: Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

23 Article Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. 2016

Deng, Yun / Zhao, Jian / Sakurai, Daisuke / Sestak, Andrea L / Osadchiy, Vadim / Langefeld, Carl D / Kaufman, Kenneth M / Kelly, Jennifer A / James, Judith A / Petri, Michelle A / Bae, Sang-Cheol / Alarcón-Riquelme, Marta E / Alarcón, Graciela S / Anaya, Juan-Manuel / Criswell, Lindsey A / Freedman, Barry I / Kamen, Diane L / Gilkeson, Gary S / Jacob, Chaim O / Merrill, Joan T / Gaffney, Patrick M / Sivils, Kathy Moser / Niewold, Timothy B / Ramsey-Goldman, Rosalind / Reveille, John D / Scofield, R Hal / Stevens, Anne M / Boackle, Susan A / Vilá, Luis M / Sohn, I I Woong / Lee, Seung / Chang, Deh-Ming / Song, Yeong Wook / Vyse, Timothy J / Harley, John B / Brown, Elizabeth E / Edberg, Jeffrey C / Kimberly, Robert P / Cantor, Rita M / Hahn, Bevra H / Grossman, Jennifer M / Tsao, Betty P. ·Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. · Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. · Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. · Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. · Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea. · Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Pfizer-Universidad de Granada-Junta de Andalucía Center for Genomics and Oncological Research, Granada, Spain. · Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia. · Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA. · Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. · Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA. · Department of Medicine, University of Southern California, Los Angeles, California, USA. · Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. · Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. · Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA. · Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA. · Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, Washington, USA Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA. · Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA US Department of Veterans Affairs Medical Center, Denver, Colorado, USA. · Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico. · Taipei Veterans General Hospital, Taipei City, Taiwan. · Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Medical Research Center, Seoul National University, Seoul, Korea. · Division of Genetics and Molecular Medicine and Immunology, King's College London, London, UK. · Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Department of Human Genetics, University of California Los Angeles, Los Angeles, California, USA. ·Ann Rheum Dis · Pubmed #26783109.

ABSTRACT: OBJECTIVES: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants. METHODS: We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. RESULTS: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 CONCLUSION: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

24 Article X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. 2016

Liu, Ke / Kurien, Biji T / Zimmerman, Sarah L / Kaufman, Kenneth M / Taft, Diana H / Kottyan, Leah C / Lazaro, Sara / Weaver, Carrie A / Ice, John A / Adler, Adam J / Chodosh, James / Radfar, Lida / Rasmussen, Astrid / Stone, Donald U / Lewis, David M / Li, Shibo / Koelsch, Kristi A / Igoe, Ann / Talsania, Mitali / Kumar, Jay / Maier-Moore, Jacen S / Harris, Valerie M / Gopalakrishnan, Rajaram / Jonsson, Roland / Lessard, James A / Lu, Xianglan / Gottenberg, Jacques-Eric / Anaya, Juan-Manuel / Cunninghame-Graham, Deborah S / Huang, Andrew J W / Brennan, Michael T / Hughes, Pamela / Illei, Gabor G / Miceli-Richard, Corinne / Keystone, Edward C / Bykerk, Vivian P / Hirschfield, Gideon / Xie, Gang / Ng, Wan-Fai / Nordmark, Gunnel / Eriksson, Per / Omdal, Roald / Rhodus, Nelson L / Rischmueller, Maureen / Rohrer, Michael / Segal, Barbara M / Vyse, Timothy J / Wahren-Herlenius, Marie / Witte, Torsten / Pons-Estel, Bernardo / Alarcon-Riquelme, Marta E / Guthridge, Joel M / James, Judith A / Lessard, Christopher J / Kelly, Jennifer A / Thompson, Susan D / Gaffney, Patrick M / Montgomery, Courtney G / Edberg, Jeffrey C / Kimberly, Robert P / Alarcón, Graciela S / Langefeld, Carl L / Gilkeson, Gary S / Kamen, Diane L / Tsao, Betty P / McCune, W Joseph / Salmon, Jane E / Merrill, Joan T / Weisman, Michael H / Wallace, Daniel J / Utset, Tammy O / Bottinger, Erwin P / Amos, Christopher I / Siminovitch, Katherine A / Mariette, Xavier / Sivils, Kathy L / Harley, John B / Scofield, R Hal. ·Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. · College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA. · College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. · Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. · U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA. · Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. · U.S. Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. · Department of Ophthalmology, Howe Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. · Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, USA. · Dean McGee Eye Institute and Department of Ophthalmology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA. · Department of Clinical Laboratory Sciences, University of Texas at El Paso, El Paso, TX 79968. · Department of Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA. · Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway. · Department of Rheumatology, Haukeland University Hospital, Bergen 5021, Norway. · Valley Bone & Joint Clinic, 3035 DeMers Avenue, Grand Forks, ND 58201, USA. · Strasbourg University, Strasbourg, France. · Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia. · Division of Genetics and Molecular Medicine and Division of Immunology, Infection and Inflammatory Disease, King's College London, London. · Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA. · Sjögren's Syndrome Clinic, National Institute of Dental and Craniofacial Research, Molecular Physiology and Therapeutics Branch, National Institutes of Health, Bethesda, MD 20892, USA. · Department of Rheumatology, Université Paris-Sud, AP-HP, INSERM U1012, Le Kremlin-Bicêtre, France. · Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario. · Hospital for Special Surgery, New York, USA. · NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK. · Lunenfeld Tanenbaum and Toronto General Research Institutes, Departments of Medicine, Immunology and Molecular Genetics, University of Toronto, Toronto Ontario. · Musculoskeletal Research Group, Institute of Cellular Medicine & NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom. · Section of Rheumatology, Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Rheumatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. · Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway. · Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, USA. · Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia. · Discipline of Medicine, University of Adelaide, Adelaide, SA 5000, Australia. · Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA. · Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. · Clinic for Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany. · Sanatorio Parque, Rosario, Argentina. · Center Pfizer, University of Granada, Andalusian Government for Genomics and Oncological Research, PTS Granada, 18016, Spain. · Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL. · Center for Public Health Genomics and Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC. · Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC. · Ralph H. Johnson VA Medical Center, Charleston, SC. · Division of Rheumatology, Department of Medicine, UCLA School of Medicine. · Division of Rheumatology, Department of Medicine, University of Michigan College of Medicine, Ann Arbor, Michigan. · Division of Rheumatology, Hospital for Special Surgery and Weill Cornell Medical College, New York, NY. · Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA. · University of Chicago Pritzker School of Medicine, Chicago, IL. · Charles R. Bronfman Institute for personalized medicine, Mount Sinai Hospital, 1468 Madison Avenue, New York, NY 10029. · Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. · Rhumatologie, Responsable de l'Unité de Recherche Clinique Hôpitaux Universitaire Paris-Sud Université Paris-Sud, INSERM U1184 Head of Autoimmunity team, IMVA : Immunology of viral Infections and Autoimmune Diseases. ·Arthritis Rheumatol · Pubmed #26713507.

ABSTRACT: OBJECTIVE: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

25 Article Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans. 2016

Lessard, Christopher J / Sajuthi, Satria / Zhao, Jian / Kim, Kwangwoo / Ice, John A / Li, He / Ainsworth, Hannah / Rasmussen, Astrid / Kelly, Jennifer A / Marion, Mindy / Bang, So-Young / Joo, Young Bin / Choi, Jeongim / Lee, Hye-Soon / Kang, Young Mo / Suh, Chang-Hee / Chung, Won Tae / Lee, Soo-Kon / Choe, Jung-Yoon / Shim, Seung Cheol / Oh, Ji Hee / Kim, Young Jin / Han, Bok-Ghee / Shen, Nan / Howe, Hwee Siew / Wakeland, Edward K / Li, Quan-Zhen / Song, Yeong Wook / Gaffney, Patrick M / Alarcón-Riquelme, Marta E / Criswell, Lindsey A / Jacob, Chaim O / Kimberly, Robert P / Vyse, Timothy J / Harley, John B / Sivils, Kathy L / Bae, Sang-Cheol / Langefeld, Carl D / Tsao, Betty P. ·Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. · Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-106, USA. · Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. · Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea. · Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA. · Kyungpook National University Hospital, Daegu 700-721, Republic of Korea. · Ajou University Hospital, Suwon 443-380, Republic of Korea. · Dong-A University Hospital, Busan 602-715, Republic of Korea. · Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-749, Republic of Korea. · Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea. · Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon 305-764, Republic of Korea. · Korea National Institute of Health, Osong 361-709, Republic of Korea. · Shanghai Institute of Rheumatology, Renji Hospital, Shanghai, China 200001. · Shanghai JiaoTong University School of Medicine, Shanghai, China 200025. · Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433. · University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. · Centro de Genómica e Investigaciones Oncológicas, Pfizer-Universidad de Granada-Junta de Andalućıa, Granada 18100, Spain. · Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA, 94117, USA. · Department of Medicine, University of Southern California, Los Angeles, CA 90095. · Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, King's College London, London, UK WC2R 2LS. · Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. · US Department of Veterans Affairs Medical Center, Cincinnati, OH 45220, USA. ·Arthritis Rheumatol · Pubmed #26663301.

ABSTRACT: OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. METHODS: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. RESULTS: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. CONCLUSION: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.

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