ArticlePLoS genetics2017
Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.
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Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 2 of them syntheses that pooled it.
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56citing papers in PubMed, 2 pooled it
3.4field-weighted citation impact, top 7% of its field
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Who cites it
56 citing papers in PubMed, 2 syntheses or guidelines pooled it, 85 citations in OpenAlex.
- Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus.Nature communications · 2025Pooled it
- Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.Annals of the rheumatic diseases · 2025Pooled it
- Mitochondrial RNA-Type I Interferon Axis in Sjögren's Disease: Molecular Mechanisms and Translational Implications.International journal of molecular sciences · 2026Review
- RNA-binding proteins and ribonucleoproteins as determinants of immunity.Nature reviews. Immunology · 2026Review
- The power of genetics in decoding Sjögren's disease: current status and future development.Current opinion in immunology · 2026Review
- From Autoimmune Sialadenitis to Central Pain: Hypothesizing Shared Pathogenesis for Fibromyalgia and Primary Sjogren's Disease and Identifying Essential Screening Strategies.International journal of molecular sciences · 2025Article
- mRNA Isoforms and Variants in Health and Disease.International journal of molecular sciences · 2025Review
- Weighted Gene Co-expression Network Analysis and Machine Learning Validation for Identifying Major Genes Related to Sjogren's Syndrome.Biochemical genetics · 2025Article
- Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren's disease for cardiovascular disease.Journal of translational medicine · 2025Article
- A Distinguishable Peripheral Blood and Conjunctival Transcriptome and Gut Microbiome in Sjögren's Disease: A Pilot Study.Eye & contact lens · 2025Article
- Exploring the role of alternative splicing in the pathogenesis of Sjögren's syndrome: identification of novel isoforms associated with salivary gland immune infiltration.Genes & genomics · 2025Article
- An overview on Sjögren's syndrome and systemic lupus erythematosus' genetics.Toxicology research · 2025Review
- Risk Allele rs117026326-Mediated Alternative Splicing of GTF2I Promotes B Cell Proliferation in Primary Sjögren's Syndrome.Journal of immunology research · 2025Article
- Causal associations of Sjögren's syndrome with cardiovascular disease: A two-sample Mendelian randomization study.American heart journal plus : cardiology research and practice · 2024Article
- Get Spliced: Uniting Alternative Splicing and Arthritis.International journal of molecular sciences · 2024Review
- Oligoadenylate synthetase 1 displays dual antiviral mechanisms in driving translational shutdown and protecting interferon production.Immunity · 2024Article
- Association of endometriosis with Sjögren's syndrome: Genetic insights (Review).International journal of molecular medicine · 2024Review
- The Many Faces of Oligoadenylate Synthetases.Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research · 2023Review
- Causal associations of Sjögren's syndrome with cancers: a two-sample Mendelian randomization study.Arthritis research & therapy · 2023Article
- Mapping interindividual dynamics of innate immune response at single-cell resolution.Nature genetics · 2023Article
Corrections and comments
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Authors and funding
65 authors at 20 institutions in 9 countries.
He LiArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Tove Ragna RekstenArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
John A IceArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Jennifer A KellyArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Indra AdriantoArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Astrid RasmussenArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.ORCID http://orcid.org/0000-0001-7744-2948
Shaofeng WangArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Bo HeArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Kiely M GrundahlArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Stuart B GlennArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Corinne Miceli-RichardUniversité Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France.
Simon BowmanRheumatology Department, University Hospital Birmingham, Birmingham, United Kingdom.
Sue LesterThe Queen Elizabeth Hospital, Adelaide, South Australia, Australia.
Per ErikssonDepartment of Rheumatology, Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Maija-Leena ElorantaDepartment of Medical Sciences, Rheumatology, SciLIfeLab, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0002-8454-1351
Johan G BrunDepartment of Clinical Science, University of Bergen, 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.
Joel M GuthridgeArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Kenneth M KaufmanDivision of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.ORCID http://orcid.org/0000-0001-8195-1876
Marika KvarnströmDepartment of Medicine, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-4948-8380
Deborah S Cunninghame GrahamDepartment of Medical and Molecular Genetics, King's College London, London, United Kingdom.ORCID http://orcid.org/0000-0002-3066-6693
Ketan PatelDivision of Oral and Maxillofacial Surgery, Department of Developmental and Surgical Science, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.
Adam J AdlerArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
A Darise FarrisArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Michael T BrennanDepartment of Oral Medicine, Carolinas Medical Center, Charlotte, North Carolina, United States of America.
James ChodoshMassachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America.
Rajaram GopalakrishnanDivision of Oral Pathology, Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.
Michael H WeismanDivision of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
Swamy VenuturupalliDivision of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
Daniel J WallaceDivision of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
Kimberly S HefnerHefner Eye Care and Optical Center, Oklahoma City, Oklahoma, United States of America.
Glen D HoustonDepartment of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, Oklahoma, United States of America.
Andrew J W HuangDepartment of Ophthalmology and Visual Sciences, Washington University, St. Louis, Missouri, United States of America.ORCID http://orcid.org/0000-0003-1939-9149
Pamela J HughesDivision of Oral and Maxillofacial Surgery, Department of Developmental and Surgical Science, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.
David M LewisDepartment of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, Oklahoma, United States of America.
Lida RadfarOral Diagnosis and Radiology Department, University of Oklahoma College of Dentistry, Oklahoma City, Oklahoma, United States of America.
Evan S VistaArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Contessa E EdgarThe Biology Department, Oklahoma Baptist University, Oklahoma City, Oklahoma, United States of America.ORCID http://orcid.org/0000-0001-9701-0886
Michael D RohrerHard Tissue Research Laboratory, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.
Donald U StoneDepartment of Ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Timothy J VyseDepartment of Medical and Molecular Genetics, King's College London, London, United Kingdom.
John B HarleyDivision of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Patrick M GaffneyArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.ORCID http://orcid.org/0000-0002-1580-869X
Judith A JamesArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Sean TurnerArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Ilias AlevizosNational Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, United States of America.
Juan-Manuel AnayaCenter for Autoimmune Diseases Research, Universidad del Rosario, Bogotá, Colombia.
Nelson L RhodusDepartment of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.
Barbara M SegalDivision of Rheumatology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
Courtney G MontgomeryArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
R Hal ScofieldArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Susan KovatsArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Xavier MarietteUniversité Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France.
Lars RönnblomDepartment of Medical Sciences, Rheumatology, SciLIfeLab, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0001-9403-6503
Torsten WitteClinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
Maureen RischmuellerThe Queen Elizabeth Hospital, Adelaide, South Australia, Australia.
Marie Wahren-HerleniusDepartment of Medicine, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-0915-7245
Roald OmdalClinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
Roland JonssonBroegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.ORCID http://orcid.org/0000-0002-9588-0260
Wan-Fai NgInstitute of Cellular Medicine & NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID http://orcid.org/0000-0002-5539-388X
for UK Primary Sjögren's Syndrome Registry
Gunnel NordmarkDepartment of Medical Sciences, Rheumatology, SciLIfeLab, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0002-3829-7431
Christopher J LessardArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Kathy L SivilsArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Oklahoma Medical Research Foundation · USUniversity of Minnesota · USUppsala University · SECedars-Sinai Medical Center · USStavanger University Hospital · NOCincinnati Children's Hospital Medical Center · USHaukeland University Hospital · NOKarolinska Institutet · SEKing's College London · GBQueen Elizabeth Hospital · AUUniversité Paris-Sud · FRUniversity of Oklahoma · USCarolinas Medical Center · USHeartland Research Associates · USJohns Hopkins University · USLinköping University · SEMassachusetts Eye and Ear Infirmary · USMedizinische Hochschule Hannover · DENational Institute of Dental and Craniofacial Research · USNIHR Newcastle Biomedical Research Centre · GB
Funding
Tracking and Evaluation CoreU54GM104938 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI PAUL G SPICER · 2013 to 2026
$68.2MSupplement - Inflammatory Triggers in B Cell AutoimmunityU19AI056363 · NIAID · DUKE UNIVERSITY · PI ST. CLAIR, EUGENE WILLIAM · 2003 to 2017
$35.3MProgram Project in the Genetics of SLEP01AR049084 · NIAMS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI KIMBERLY, ROBERT P. · 2002 to 2012
$12.7MSequencingP01AI083194 · NIAID · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI KIMBERLY, ROBERT P. · 2009 to 2013
$9.6MPathogenic B Cells in Sjogren's SyndromeP50AR060804 · NIAMS · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI MONTGOMERY, COURTNEY · 2011 to 2015
$7.9MSNP Confirmation and High Throughput Genotyping CoreP30AR053483 · NIAMS · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI CHAKRAVARTY, ELIZA F · 2007 to 2017
$6.7MPre-Clinical Studies to Identify SLE Therapeutic TargetsU19AI082714 · NIAID · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI GAFFNEY, PATRICK M · 2009 to 2018
$6.2MQuantitative Analysis Core P30GM110766 · NIGMS · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI GAFFNEY, PATRICK M · 2014 to 2018
$6.1MMolecular Mechanisms and Genetics of AutoimmunityP20GM103456 · NIGMS · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI GAFFNEY, PATRICK M · 2012 to 2013
$4.8MCandidate Causal Variants in Systemic Lupus ErythematosusRC2AR058959 · NIAMS · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI GAFFNEY, PATRICK M, WAKELAND, EDWARD K. · 2009 to 2010
$4.3MGenetic Linkage in LupusR37AI024717 · NIAID · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI HARLEY, JOHN BARKER · 2005 to 2014
$4.2MMolecular Basis of Immunity - Kirschtein-NRSAT32AI007633 · NIAID · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI CUNNINGHAM, MADELEINE W. · 2001 to 2022
$4.0MMedical Research Council G0800629NCRR NIH HHS S10 RR026735NCRR NIH HHS S10 RR027190NIAID NIH HHS P01 AI083194NIAID NIH HHS R37 AI024717NIAID NIH HHS T32 AI007633NIAID NIH HHS U01 AI101934NIAID NIH HHS U19 AI056363NIAID NIH HHS U19 AI082714NIAMS NIH HHS P01 AR049084NIAMS NIH HHS P30 AR053483NIAMS NIH HHS P50 AR060804NIAMS NIH HHS R01 AR065953NIAMS NIH HHS R03 AR065786NIAMS NIH HHS RC2 AR058959NIDCR NIH HHS R01 DE015223NIDCR NIH HHS R01 DE018209NIGMS NIH HHS P20 GM103456NIGMS NIH HHS P30 GM103510NIGMS NIH HHS P30 GM110766NIGMS NIH HHS U54 GM104938
Abstract
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
Indexed as
2',5'-Oligoadenylate SynthetaseAllelesAlternative SplicingFemaleGene Expression RegulationGenetic Association StudiesGenetic Predisposition to DiseaseHumansInterferon Type IMaleQuantitative Trait LociSjogren's SyndromeVirus Diseases2',5'-Oligoadenylate SynthetaseInterferon Type IOAS1 protein, human
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