ArticleAmerican journal of human genetics2026
A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity.
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Article in American journal of human genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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65 authors.
Samuel J VirolainenCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Kathryn CreightonDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Rutgers MD-PhD Program, New Jersey Medical School, Newark, NJ 03103, USA.
Maryam DashtiahangarDepartment of Biology, Boston University, Boston, MA 02215, USA.
Durga KrishnamurthyCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Lois ParksCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Carmy ForneyCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Britney AmpaduCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Harvard College, Harvard University, Cambridge, MA 02138, USA.
Akshata N RudrapatnaDivision of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA; Biomedical Informatics Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Katelyn A DunnCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Sreeja ParameswaranCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Hayley K HesseCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Xiaoting ChenCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Andrew VonHandorfCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Lee E EdsallCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Cailing YinCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Arthur LynchCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Olivia GittensCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Arame A DioufCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Sydney H JonesCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Matthew HassCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Ellen JavierCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Omer DonmezCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Yasine KeddariCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Oded DanzingerDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Harsha SeelamneniCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Bahram Namjou-KhalesCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Hannah C AinsworthDepartment of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA.
Mary E ComeauDepartment of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA.
Miranda C MarionDepartment of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA.
Stuart B GlennGenes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Swapan K NathArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Barry I FreedmanSection on Nephrology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Betty P TsaoDivision of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
Diane L KamenDivision of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
Elizabeth E BrownDivision of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Gary S GilkesonDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Graciela S AlarcónDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
John D ReveilleDivision of Rheumatology, University of Texas McGovern Medical School, Houston, TX 77030, USA.
Judith A JamesArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Lindsey A CriswellGenomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Luis M ViláDivision of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA.
Marta E Alarcón-RiquelmeInstitute for Environmental Medicine, Karolinska Institutet, 171 67 Solna, Sweden; Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Government, 18016 Granada, Spain.
Michelle PetriDivision of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
R Hal ScofieldArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Medicine, College of Medicine, University of Oklahoma, Oklahoma City, OK 73104, USA; Oklahoma City Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
Robert P KimberlyDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Rosalind Ramsey-GoldmanDivision of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Sang-Cheol BaeDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea; Hanyang University Institute for Rheumatology Research and Hanyang Institute of Bioscience and Biotechnology, Seoul 04763, Korea.
Deborah Cunninghame GrahamDivision of Rheumatology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
Timothy J VyseDepartment of Medical & Molecular Genetics, Guy's Hospital, King's College London, London SE1 9RT, UK.
Joel M GuthridgeArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Patrick M GaffneyGenes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Carl D LangefeldDepartment of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA.
Jennifer A KellyGenes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Kenneth M KaufmanCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Kathy L SivilsThe Janssen Pharmaceutical Companies of Johnson & Johnson, Raritan, NJ 08869, USA.
John B HarleyResearch Service, US Department of Veterans Affairs Medical Center, Cincinnati, OH 45229, USA.
Nan ShenShanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Lucinda P LawsonDivision of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Yuriy BaglaenkoCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Emily R MiraldiImmunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Brad R RosenbergDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Trevor SiggersDepartment of Biology, Boston University, Boston, MA 02215, USA.
Stephen N WaggonerCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Matthew T WeirauchCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: matthew.weirauch@cchmc.org.
Leah C KottyanCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: leah.kottyan@cchmc.org.
Funding
TSLP, IL-9-producing mucosal mast cells, and allergic inflammationU19AI070235 · NIAID · CINCINNATI CHILDRENS HOSP MED CTR · PI Gurjit K. Khurana Hershey · 2006 to 2026
$31.3MResearch Project 3: Role of Posttranslational Protein Modifications in the Pathogenesis of Ebola Virus DiseaseP01AI150585 · NIAID · UNIVERSITY OF TEXAS MED BR GALVESTON · PI BUKREYEV, ALEXANDER · 2021 to 2025
$11.3MHLA GENE COMPLEMENTATION IN PRIMARY SJOGREN'S AND LUPUSR01AI024717 · NIAID · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI KOTTYAN, LEAH CLAIRE, WEIRAUCH, MATTHEW TYSON · 1987 to 2025
$7.8MTissue Repository CoreP30AR070549 · NIAMS · CINCINNATI CHILDRENS HOSP MED CTR · PI Leah Claire Kottyan · 2016 to 2026
$7.7MPolygenic Risk Scores for Healthier African American FamiliesU01HG011172 · NHGRI · CINCINNATI CHILDRENS HOSP MED CTR · PI Leah Claire Kottyan, LISA J MARTIN · 2020 to 2026
$7.2MGene Regulation as a Foundation for Autoimmune Disease PreventionU01AI130830 · NIAID · CINCINNATI CHILDRENS HOSP MED CTR · PI WEIRAUCH, MATTHEW TYSON · 2017 to 2021
$7.2MBIOCHEMICAL AND GENETIC ANALYSIS OF NOTCH SIGNALINGR01GM055479 · NIGMS · WASHINGTON UNIVERSITY · PI KOPAN, RAPHAEL, WEIRAUCH, MATTHEW TYSON · 1996 to 2021
$6.4MDynamic regulatory network models of human response to influenza virusU01AI150748 · NIAID · UNIVERSITY OF CALIFORNIA-IRVINE · PI MARAZZI, IVAN, MIRALDI, EMILY · 2020 to 2024
$5.8MBinding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic MechanismsR01NS099068 · NINDS · CINCINNATI CHILDRENS HOSP MED CTR · PI Leah Claire Kottyan, Matthew Tyson Weirauch · 2017 to 2026
$4.2MGenomics of Inflammatory Bowel DiseaseR01AI148276 · NIAID · CINCINNATI CHILDRENS HOSP MED CTR · PI KOTTYAN, LEAH CLAIRE · 2019 to 2023
$3.9MClinical applications of urine proteomics to lupus nephritisR01DK134625 · NIDDK · JOHNS HOPKINS UNIVERSITY · PI Andrea Fava · 2023 to 2026
$2.8MBlocking granzyme-mediated immune suppression to enhance HIV vaccine efficacyR01AI176519 · NIAID · CINCINNATI CHILDRENS HOSP MED CTR · PI Vijayakumar Velu, Stephen N. Waggoner · 2023 to 2026
$2.8MNHGRI NIH HHS R01 HG010730NHGRI NIH HHS U01 HG011172NHGRI NIH HHS U24 HG013078NIAID NIH HHS P01 AI150585NIAID NIH HHS R01 AI024717NIAID NIH HHS R01 AI148276NIAID NIH HHS R01 AI176519NIAID NIH HHS R01 AI205712NIAID NIH HHS U01 AI130830NIAID NIH HHS U01 AI150748NIAID NIH HHS U19 AI070235NIAMS NIH HHS P30 AR070549NIAMS NIH HHS R01 AR073228NIDDK NIH HHS R01 DK107502NIDDK NIH HHS R01 DK134625NIGMS NIH HHS R01 GM055479NINDS NIH HHS R01 NS099068
Abstract
Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with systemic lupus erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within IRF7. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA-binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in interferon-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of the corresponding risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits.
Indexed as
AutoimmunityHaplotypesInterferon-alphaInterferon Regulatory Factor-7Lupus Erythematosus, SystemicAnimalsGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMicePolymorphism, Single NucleotideInterferon-alphaInterferon Regulatory Factor-7IRF7 protein, humanIrf7 protein, mouseancient DNAantiviral responseautoreactivityhost defenseinterferon regulatory factorspopulation geneticssystemic lupus erythematosustranscription
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