ArticleHuman molecular genetics2015
The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
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In one paragraph
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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43citing papers in PubMed, 1 pooled it
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 89 citations in OpenAlex.
- Unfolding the pathogenesis of scleroderma through genomics and epigenomics.Journal of autoimmunity · 2017Pooled it
- Rare variants in non-coding regulatory regions of the genome that affect gene expression in systemic lupus erythematosus.Scientific reports · 2019Trial
- A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.Human molecular genetics · 2018Trial
- The power of genetics in decoding Sjögren's disease: current status and future development.Current opinion in immunology · 2026Review
- Multidimensional mapping of stimulation-responsive regulatory elements and candidate causal variants in T cell activation.Science advances · 2026Article
- Shared genetic architecture and potential comorbid mechanisms between rheumatoid arthritis and idiopathic pulmonary fibrosis.Clinical rheumatology · 2026Article
- An overview on Sjögren's syndrome and systemic lupus erythematosus' genetics.Toxicology research · 2025Review
- Discovery of new myositis genetic associations through leveraging other immune-mediated diseases.HGG advances · 2024Article
- Article
- The 330 risk loci known for systemic lupus erythematosus (SLE): a review.Frontiers in lupus · 2024Article
- Investigating the causal relationship and potential shared diagnostic genes between primary biliary cholangitis and systemic lupus erythematosus using bidirectional Mendelian randomization and transcriptomic analyses.Frontiers in immunology · 2024Article
- Pervasive Sharing of Causal Genetic Risk Factors Contributes to Clinical and Molecular Overlap between Sjögren's Disease and Systemic Lupus Erythematosus.International journal of molecular sciences · 2023Article
- A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren's Syndrome.Clinical reviews in allergy & immunology · 2023Review
- An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping.Nature communications · 2023Article
- Modeling of horizontal pleiotropy identifies possible causal gene expression in systemic lupus erythematosus.Frontiers in lupus · 2023Article
- Comparative immune-relevant transcriptome reveals the evolutionary basis of complex traits.iScience · 2022Article
- Autoimmune liver diseases in systemic rheumatic diseases.World journal of gastroenterology · 2022Review
- Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.Translational research : the journal of laboratory and clinical medicine · 2022Article
- Systemic lupus erythematosus as a genetic disease.Clinical immunology (Orlando, Fla.) · 2022Article
- Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.medRxiv : the preprint server for health sciences · 2021Article
Corrections and comments
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Authors and funding
84 authors at 20 institutions in 13 countries.
Leah C KottyanDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA leah.kottyan@cchmc.org.
Erin E ZollerDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and leah.kottyan@cchmc.org.
Jessica BeneDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and.
Xiaoming LuDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and.
Jennifer A KellyArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Andrew M RupertDivision of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Christopher J LessardArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology and.
Samuel E VaughnDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and.
Miranda MarionDepartment of Biostatistical Sciences and Center for Public Health Genomics and.
Matthew T WeirauchDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Bahram NamjouDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and.
Adam AdlerArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Astrid RasmussenArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Stuart GlennArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Courtney G MontgomeryArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Gideon M HirschfieldNIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.
Gang XieMount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada.
Catalina ColtescuLiver Centre, Toronto Western Hospital, Toronto, ON, Canada.
Chris AmosDepartment of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
He LiArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology and.
John A IceArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Swapan K NathArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Xavier MarietteDepartment of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France.
Simon BowmanRheumatology Department, University Hospital Birmingham, Birmingham, UK.
UK Primary Sjögren's Syndrome Registry
Maureen RischmuellerThe Queen Elizabeth Hospital, Adelaide, Australia.
Sue LesterThe Queen Elizabeth Hospital, Adelaide, Australia The University of Adelaide, Adelaide, Australia.
Johan G BrunInstitute of Internal Medicine, University of Bergen, Bergen, Norway Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.
Lasse G GøranssonClinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
Erna HarboeClinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
Roald OmdalClinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
Deborah S Cunninghame-GrahamDepartment of Medical and Molecular Genetics, King's College London, London, UK.
Tim VyseDepartment of Medical and Molecular Genetics, King's College London, London, UK.
Corinne Miceli-RichardDepartment of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France.
Michael T BrennanDepartment of Oral Medicine, Carolinas Medical Center, Charlotte, NC, USA.
James A LessardValley Bone and Joint Clinic, Grand Forks, ND, USA.
Marie Wahren-HerleniusDepartment of Medicine, Karolinska Institute, Stockholm, Sweden.
Marika KvarnströmDepartment of Medicine, Karolinska Institute, Stockholm, Sweden.
Gabor G IlleiNational Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
Torsten WitteHannover Medical School, Hanover, Germany.
Roland JonssonDepartment of Rheumatology, Haukeland University Hospital, Bergen, Norway Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway.
Per ErikssonDepartment of Rheumatology, Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Gunnel NordmarkDepartment of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden.
Wan-Fai NgInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
UK Primary Sjögren's Syndrome Registry
Juan-Manuel AnayaCenter for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia.
Nelson L RhodusDepartment of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, MN, USA.
Barbara M SegalDivision of Rheumatology, University of Minnesota Medical School, Minneapolis, MN, USA.
Joan T MerrillArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Judith A JamesArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Joel M GuthridgeArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
R Hal ScofieldArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Division of Veterans Affairs Medical Center, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Marta Alarcon-RiquelmeArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain.
Sang-Cheol BaeDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.
Susan A BoackleDivision of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA.
Lindsey A CriswellDivision of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA.
Gary GilkesonDivision of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
Diane L KamenDivision of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
Chaim O JacobDivison of Gastrointestinal and Liver Diseases, Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Robert KimberlyDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Elizabeth BrownDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Jeffrey EdbergDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Graciela S AlarcónDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
John D ReveilleDivision of Rheumatology and Clinical Immunogenetics, The Univeristy of Texas Health Science Center at Houston, Houston, TX, USA.
Luis M ViláUniversity of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA.
Michelle PetriDivision of Rheumatology, Johns Hopkins, Baltimore, MD, USA.
Rosalind Ramsey-GoldmanDivision of Rheumatology, Northwestern University, Chicago, IL, USA.
Barry I FreedmanWake Forest School of Medicine, Winston-Salem, NC, USA.
Timothy NiewoldDivision of Rheumatology and Immunology, Mayo Clinic, Rochester, MN, USA.
Anne M StevensUniversity of Washington and Seattle Children's Hospital, Seattle, WA, USA.
Betty P TsaoDavid Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Jun YingMD Anderson Cancer Center, University of Texas, Houston, TX, USA.
Maureen D MayesMD Anderson Cancer Center, University of Texas, Houston, TX, USA.
Olga Y GorlovaMD Anderson Cancer Center, University of Texas, Houston, TX, USA.
Ward WakelandUniversity of Texas Southwestern Medical School, Dallas, TX, USA.
Timothy RadstakeDepartment of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Ezequiel MartinInstituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and.
Javier MartinInstituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and.
Katherine SiminovitchMount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada Department of Medicine, University of Toronto, Toronto, ON, Canada.
Kathy L Moser SivilsArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Patrick M GaffneyArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Carl D LangefeldDepartment of Biostatistical Sciences and Center for Public Health Genomics and.
John B HarleyDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA.
Kenneth M KaufmanDivision of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA.
Oklahoma Medical Research Foundation · USAutoimmune Technologies (United States) · USUnited States Department of Veterans Affairs · USThe University of Texas MD Anderson Cancer Center · USInserm · FRKarolinska Institutet · SEMedical University of South Carolina · USMount Sinai Hospital · CAStavanger University Hospital · NOUniversity of Alabama at Birmingham · USCincinnati Children's Hospital Medical Center · USHaukeland University Hospital · NOKing's College London · GBLinköping University · SENorthwestern University · USQueen Elizabeth Hospital · AUSeattle Children's Hospital · USUniversity of Minnesota · USUniversity of Southern California · USVeterans Health Administration · US
Funding
Translational Engineering in Cancer (TEC)P30CA023108 · NCI · DARTMOUTH COLLEGE · PI Steven D Leach · 1985 to 2026
$91.3MTracking and Evaluation CoreU54GM104938 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI PAUL G SPICER · 2013 to 2026
$68.2MNorthwestern University Clinical and Translational Science Institute (NUCATS)UL1TR001422 · NCATS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI D'AQUILA, RICHARD · 2015 to 2023
$56.8MColorado Clinical and Translational Sciences InstituteUL1TR001082 · NCATS · UNIVERSITY OF COLORADO DENVER · PI SOKOL, RONALD J. · 2013 to 2017
$48.0MUAB Center for Clinical and Translational Science (CCTS)UL1TR001417 · NCATS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI KIMBERLY, ROBERT P. · 2015 to 2018
$31.4MZD1839 FOR MALIGNANT ASTROCYTOMA OR GLIOBLASTOMA AND MENINGIOMAM01RR000079 · NCRR · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KESSLER, DAVID A · 1985 to 2006
$26.0MMULTIDISCIPLINARY CLINICAL AND TRANSLATIONAL SCIENCE (MCTS) PROGRAM (UL1)UL1RR025741 · NCRR · NORTHWESTERN UNIVERSITY AT CHICAGO · PI GREENLAND, PHILIP · 2008 to 2011
$24.7MRelation Between In-utero Vitamin D and Immune Function in Early Childhood P20GM104416 · NIGMS · DARTMOUTH COLLEGE · PI CHRISTENSEN, BROCK CLARKE · 2013 to 2022
$23.7MVALIDATING NOVEL GENES IMPLICATED IN LEUKOCYTE CHEMOTAXISP20RR020143 · NCRR · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI GAFFNEY, PATRICK M · 2004 to 2011
$21.0MColorado Clinical and Translational Science Institute (UL1)UL1TR000154 · NCATS · UNIVERSITY OF COLORADO DENVER · PI SOKOL, RONALD J. · 2012 to 2013
$20.4MCTSA INFRASTRUCTURE FOR PEDIATRIC RESEARCHUL1RR026314 · NCRR · UNIVERSITY OF CINCINNATI · PI HEUBI, JAMES E. · 2009 to 2011
$14.3MCenter for Clinical and Translational Sciences (CCTS)UL1TR000371 · NCATS · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI MCPHERSON, DAVID D · 2012 to 2016
$13.4MBLRD VA I01 BX001834CIHR MOP74621Medical Research Council G0800629NCATS NIH HHS TR000165NCATS NIH HHS UL1 TR000077NCATS NIH HHS UL1 TR000154NCATS NIH HHS UL1 TR000165NCATS NIH HHS UL1 TR000371NCATS NIH HHS UL1 TR001082NCATS NIH HHS UL1 TR001417NCATS NIH HHS UL1 TR001422NCI NIH HHS P30 CA023108NCRR NIH HHS 1RR025741NCRR NIH HHS M01 RR000079NCRR NIH HHS P20 RR020143NCRR NIH HHS RR-000079NCRR NIH HHS RR020143NCRR NIH HHS RR026314NCRR NIH HHS RR027190NCRR NIH HHS RR029882NCRR NIH HHS S10 RR027190NCRR NIH HHS UL1 RR025741NCRR NIH HHS UL1 RR026314NCRR NIH HHS UL1 RR029882NIAID NIH HHS AI024717NIAID NIH HHS AI031584NIAID NIH HHS AI070304NIAID NIH HHS AI082714NIAID NIH HHS AI083194NIAID NIH HHS AI094377NIAID NIH HHS AI101934NIAID NIH HHS K24 AI078004NIAID NIH HHS P01 AI083194NIAID NIH HHS R01 AI024717NIAID NIH HHS R01 AI031584NIAID NIH HHS R21 AI070304NIAID NIH HHS R21 AI094377NIAID NIH HHS R37 AI024717NIAID NIH HHS U01 AI101934NIAID NIH HHS U19 AI082714NIAMS NIH HHS AR 002138NIAMS NIH HHS AR042460NIAMS NIH HHS AR043418NIAMS NIH HHS AR048940NIAMS NIH HHS AR049084NIAMS NIH HHS AR052300NIAMS NIH HHS AR053483NIAMS NIH HHS AR057172NIAMS NIH HHS AR058959NIAMS NIH HHS AR060366NIAMS NIH HHS AR0608040NIAMS NIH HHS AR062277NIAMS NIH HHS AR062755NIAMS NIH HHS AR065626NIAMS NIH HHS AR30692NIAMS NIH HHS AR43727NIAMS NIH HHS K24 AR002138NIAMS NIH HHS N01 AR062277NIAMS NIH HHS P01 AR049084NIAMS NIH HHS P30 AR053483NIAMS NIH HHS P50 AR048940NIAMS NIH HHS P50 AR060804NIAMS NIH HHS P60 AR030692NIAMS NIH HHS P60 AR053308NIAMS NIH HHS P60 AR062755NIAMS NIH HHS R01 AR042460NIAMS NIH HHS R01 AR043727NIAMS NIH HHS R01 AR052300NIAMS NIH HHS R01 AR055258NIAMS NIH HHS R01 AR057172NIAMS NIH HHS R01 AR060366NIAMS NIH HHS R21 AR065626NIAMS NIH HHS RC2 AR058959NIDCR NIH HHS DE015223NIDCR NIH HHS DE018209NIDCR NIH HHS DE018209-02NIDCR NIH HHS R01 DE015223NIDCR NIH HHS R01 DE018209NIGMS NIH HHS GM103510NIGMS NIH HHS P20 GM104416NIGMS NIH HHS P30 GM103510NIGMS NIH HHS U54 GM104938
Abstract
Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
Indexed as
Autoimmune DiseasesBayes Theorembeta KaryopherinsCase-Control StudiesCohort StudiesDNA-Binding ProteinsHaplotypesHumansInterferon Regulatory FactorsLupus Erythematosus, SystemicMalePolymorphism, Single NucleotidePromoter Regions, Geneticbeta KaryopherinsDNA-Binding ProteinsInterferon Regulatory FactorsIRF5 protein, humanTNPO3 protein, humanZBTB3 protein, human
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