A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity
Year: 2026
Type: article
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.
Authors: Samuel J. Virolainen, Kathryn Creighton, Maryam Dashtiahangar, Durga Krishnamurthy, Lois Parks, Carmy Forney, Britney Ampadu, Akshata N. Rudrapatna, Katelyn A. Dunn, Sreeja Parameswaran, Hayley K. Hesse, Xiaoting Chen, Andrew VonHandorf, Lee E. Edsall, Cailing Yin, Arthur Lynch, Olivia Gittens, Arame A. Diouf, Sydney H. Jones, Matthew Hass, Ellen Javier, Omer Donmez, Yasine Keddari, Oded Danzinger, Harsha Seelamneni, Bahram Namjou-Khales, Hannah C. Ainsworth, Mary E. Comeau, Miranda C. Marion, Stuart B. Glenn, Swapan K. Nath, Barry I. Freedman, Betty P. Tsao, Diane L. Kamen, Elizabeth E. Brown, Gary S. Gilkeson, Graciela S. Alarcón, John D. Reveille, Judith A. James, Lindsey A. Criswell, Luis M. Vilá, Marta E. Alarcón-Riquelme, Michelle Petri, R. Hal Scofield, Robert P. Kimberly, Rosalind Ramsey-Goldman, Sang-Cheol Bae, Deborah Cunninghame Graham, Timothy J. Vyse, Joel M. Guthridge, Patrick M. Gaffney, Carl D. Langefeld, Jennifer A. Kelly, Kenneth M. Kaufman, Kathy L. Sivils, John B. Harley, Nan Shen, Lucinda P. Lawson, Yuriy Baglaenko, Emily R. Miraldi, Brad R. Rosenberg, Trevor Siggers, Stephen N. Waggoner, Matthew T. Weirauch, Leah C. Kottyan
Institutions: Cincinnati Children's Hospital Medical Center, University of Cincinnati, Rutgers, The State University of New Jersey, Rutgers New Jersey Medical School, Icahn School of Medicine at Mount Sinai, Boston University, Harvard University, Wake Forest University Health Sciences, Wake Forest University, Oklahoma Medical Research Foundation, Atrium Health Wake Forest Baptist, Medical University of South Carolina, University of Alabama at Birmingham, National Institutes of Health, National Human Genome Research Institute, University of Puerto Rico, Medical Sciences Campus, Universidad de Granada, Karolinska Institutet, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research, Johns Hopkins University, Johns Hopkins Medicine, United States Department of Veterans Affairs, Oklahoma City VA Medical Center, University of Oklahoma, Northwestern University, Hanyang University Seoul Hospital, Hanyang University Hospital for Rheumatic Disease, University of Colorado Anschutz, Guy's Hospital, King's College London, Veterans Health Administration, Cincinnati VA Medical Center, Shanghai Jiao Tong University, Renji Hospital
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,150
Funders: U.S. Department of Defense, Johns Hopkins University, National Research Foundation, Ministry of Education, National Research Foundation of Korea, National Institutes of Health, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1103682706, CisBP and CisBP-RNA: web resources for protein-DNA and protein-RNA binding models, G1698488130, G2376932754, Virus-driven human gene misregulation in disease, Genomics of Inflammatory Bowel Disease, G72630307, G7301145059, G9000016495, G9000029701, G9000034084, G9000042482, G9000055200, G9000074399, G9000082378, G9000101542, G9000112267, G9000116733, G9000159478, G9000169229, G9000185946, G9000199090, G9000309704, G9000353464, Clinical applications of urine proteomics to lupus nephritis, Cincinnati Rheumatic Diseases Resource Center, Molecular Mechanisms of the Dysregulated Immune Response to Ebola Virus
OpenAlex ID: W7212270281