{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T02:06:58Z","timestamp":1769306818682,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,22]]},"group-title":"Rheumatology","reference-count":116,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,22]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>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 the IRF7 gene. 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 IFN-\u03b1 production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of a homologous 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 genetic IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits.<\/jats:p>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:p>\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:label>\u25cf<\/jats:label>\n                        <jats:p>\n                          Genetic analysis using modern and evolutionary datasets identifies a persistent and highly prevalent lupus-associated coding haplotype in\n                          <jats:italic>IRF7<\/jats:italic>\n                          at 11p15\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>\u25cf<\/jats:label>\n                        <jats:p>\n                          The\n                          <jats:italic>IRF7<\/jats:italic>\n                          lupus risk haplotype increases IFN-\u03b1 production by monocytes and airway epithelial cells\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>\u25cf<\/jats:label>\n                        <jats:p>\n                          The\n                          <jats:italic>IRF7<\/jats:italic>\n                          lupus risk haplotype increases IRF7 DNA binding strength and alters DNA sequence specificity\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>\u25cf<\/jats:label>\n                        <jats:p>\n                          A homologous lupus risk variant in mouse\n                          <jats:italic>Irf7<\/jats:italic>\n                          enhances control of vesicular stomatitis virus and exacerbates autoantibody production\n                        <\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.21.26344474","type":"posted-content","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T19:40:19Z","timestamp":1769110819000},"source":"Crossref","is-referenced-by-count":0,"title":["A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-\u03b1, enhancing antiviral defense and exacerbating autoimmunity"],"prefix":"10.64898","author":[{"given":"Samuel J.","family":"Virolainen","sequence":"first","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Immunology Graduate Program, University of Cincinnati College of Medicine. Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Creighton","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Rutgers MD-PhD Program, New Jersey Medical School. Newark, NJ 03103"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Dashtiahangar","sequence":"additional","affiliation":[{"name":"Department of Biology, Boston University, Boston, MA 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Durga","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lois","family":"Parks","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Immunology Graduate Program, University of Cincinnati College of Medicine. Cincinnati, OH 45229"},{"name":"Division of Allergy and Immunology, Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmy","family":"Forney","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Division of Allergy and Immunology, Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britney","family":"Ampadu","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Harvard College, Harvard University, Cambridge, MA 02138"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akshata N.","family":"Rudrapatna","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Cincinnati Children\u2019s Hospital. Cincinnati, OH, 45229"},{"name":"Biomedical Informatics Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katelyn A.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Division of Allergy and Immunology, Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sreeja","family":"Parameswaran","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Division of Allergy and Immunology, Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayley K.","family":"Hesse","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. Cincinnati Children\u2019s Hospital Medical Center. Cincinnati, OH 45229"},{"name":"Division of Allergy and Immunology, Cincinnati Children\u2019s Hospital Medical Center. 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Hal","family":"Scofield","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104"},{"name":"Department of Medicine, College of Medicine, University of Oklahoma, Oklahoma City, OK 73104"},{"name":"Oklahoma City Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert P.","family":"Kimberly","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosalind","family":"Ramsey-Goldman","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang-Cheol","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea"},{"name":"Hanyang University Institute for Rheumatology Research and Hanyang Institute of Bioscience and Biotechnology, Seoul 04763, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah Cunninghame","family":"Graham","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, School of Medicine, University of Colorado, Aurora, CO 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy J.","family":"Vyse","sequence":"additional","affiliation":[{"name":"Department of Medical & Molecular Genetics, Guy\u2019s Hospital, King\u2019s College London, London SE1 9RT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel M.","family":"Guthridge","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick M.","family":"Gaffney","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl D.","family":"Langefeld","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina"},{"name":"Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer A.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth M.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology. 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