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Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

Title: Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland
Authors: Wiley, Mandi M.; Radziszewski, Marcin; Khatri, Bhuwan; Joachims, Michelle L.; Tessneer, Kandice L.; Stolarczyk, Anna M.; Yao, Songyuan; Li, James; Pritchett-Frazee, Cherilyn; Johnston, Audrey A.; Rasmussen, Astrid; Anaya, Juan-Manuel; Aqrawi, Lara A.; Bae, Sang-Cheol; Baecklund, Eva; Björk, Albin; Brun, Johan G.; Bucher, Sara Magnusson; Dand, Nick; Eloranta, Maija-Leena; Engelke, Fiona; Forsblad-d'Elia, Helena; Fugmann, Cecilia; Glenn, Stuart B.; Gong, Chen; Gottenberg, Jacques-Eric; Hammenfors, Daniel; Imgenberg-Kreuz, Juliana; Jensen, Janicke Liaaen; Johnsen, Svein Joar Auglænd; Jonsson, Malin V.; Kelly, Jennifer A.; Khanam, Sharmily; Kim, Kwangwoo; Kvarnström, Marika; Mandl, Thomas; Martín, Javier; Morris, David L.; Nocturne, Gaetane; Norheim, Katrine Brække; Olsson, Peter; Palm, Øyvind; Pers, Jacques-Olivier; Rhodus, Nelson L.; Sjöwall, Christopher; Skarstein, Kathrine; Taylor, Kimberly E.; Tombleson, Phil; Thorlacius, Gudny Ella; Venuturupalli, Swamy R.; Vital, Edward M.; Wallace, Daniel J.; Radfar, Lida; Brennan, Michael T.; James, Judith A.; Scofield, R. Hal; Gaffney, Patrick M.; Criswell, Lindsey A.; Jonsson, Roland; Appel, Silke; Eriksson, Per; Bowman, Simon J; Omdal, Roald; Rönnblom, Lars; Warner, Blake M.; Rischmueller, Maureen; Witte, Torsten; Farris, A. Darise; Mariette, Xavier; Shiboski, Caroline H; Wahren-Herlenius, Marie; Alarcón-Riquelme, Marta E.; Ng, Wan-Fai; Sivils, Kathy L.; Guthridge, Joel M.; Adrianto, Indra; Vyse, Timothy J.; Tsao, Betty P.; Nordmark, Gunnel; Lessard, Christopher J.
Publisher Information: Umeå universitet, Institutionen för folkhälsa och klinisk medicin; Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), OK, Oklahoma City, United States; Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), OK, Oklahoma City, United States; University of Oklahoma Health Sciences Center, OK, Oklahoma City, United States; Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), OK, Oklahoma City, United States; Arthritis and Clinical Immunology Research Program, OMRF, OK, Oklahoma City, United States; Arthritis and Clinical Immunology Research Program, OMRF, OK, Oklahoma City, United States; Universidad de la Costa, Barranquilla, Colombia; Kristiania University College, Oslo, Norway; University of Oslo, Oslo, Norway; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology Research and Hanyang Institute of Bioscience and Biotechnology, Seoul, South Korea; Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Karolinska Institutet, Stockholm, Sweden; Haukeland University Hospital, Bergen, Norway; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway; Örebro University, Örebro, Sweden; Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, United Kingdom; Hannover Medical School, Hannover, Germany; University of Gothenburg, Gothenburg, Sweden; Hôspitaux Universitaires de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Regenerative NanoMedicine, Institut National de la Santé et de la Recherche Médicale (INSERM), Strasbourg, France; University of Oslo, Oslo, Norway; Stavanger University Hospital, Stavanger, Norway; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway; Kyung Hee University, Seoul, South Korea; Karolinska Institutet, Stockholm, Sweden; Academic Specialist Center, Center for Rheumatology, Stockholm Health Services, Stockholm, Sweden; Skane University Hospital Malmö, Lund University, Malmö, Sweden; Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain; Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France; Assistance Publique – Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway; Stavanger University Hospital, Stavanger, Norway; Oslo University Hospital, Oslo, Norway; LBAI, UMR1227, University of Brest, INSERM, Brest, France; CHU de Brest, Brest, France; University of Minnesota, MN, Minneapolis, United States; Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, Sweden; University of California San Francisco, CA, San Francisco, United States; Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, United Kingdom; NIHR GSTFT/KCL Biomedical Research Centre, London, United Kingdom; Cedars-Sinai Medical Center, CA, Los Angeles, United States; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom; NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospital NHS Trust, Leeds, United Kingdom; College of Dentistry, University of Oklahoma Health Sciences Center, OK, Oklahoma City, United States; Atrium Health Carolinas Medical Center, NC, Charlotte, United States; Wake Forest University School of Medicine, NC, Winston-Salem, United States; University of Oklahoma Health Sciences Center, OK, Oklahoma City, United States; Arthritis and Clinical Immunology Research Program, OMRF, OK, Oklahoma City, United States; University of Oklahoma Health Sciences Center, OK, Oklahoma City, United States; Arthritis and Clinical Immunology Research Program, OMRF, OK, Oklahoma City, United States; US Department of Veteran Affairs Medical Center, OK, Oklahoma City, United States; University of California San Francisco, CA, San Francisco, United States; National Human Genome Research Institute, National Institutes of Health, MD, Bethesda, United States; University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; Salivary Disorders Unit and NIDCR Sjögren's Disease Clinic, National Institute of Dental and Craniofacial Research, MD, Bethesda, United States; Karolinska Institutet, Stockholm, Sweden; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway; Karolinska Institutet, Stockholm, Sweden; GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain; NIHR Newcastle Biomedical Research Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom; University College Cork, Cork, Ireland; Henry Ford Health, MI, Detroit, United States; Michigan State University, MI, East Lansing, United States; Henry Ford Health + Michigan State University Health Sciences, MI, East Lansing, United States; Medical University of South Carolina, SC, Charleston, United States; The Queen Elizabeth Hospital and Medical School, University of Adelaide, SA, Australia
Publication Year: 2025
Collection: Umeå University: Publications (DiVA)
Subject Terms: Medical Genetics and Genomics; Medicinsk genetik och genomik; Rheumatology; Reumatologi; Autoimmunity and Inflammation; Autoimmunitet och inflammation
Description: Objectives: Sjögren's disease (SjD) and systemic lupus erythematosus (SLE) share genetic risk at the DDX6-CXCR5 locus (11q23.3). Identifying and functionally characterising shared SNPs spanning this locus can provide new insights into common genetic mechanisms of autoimmunity. Methods: Transdisease meta-analyses, fine-mapping, and bioinformatic analyses prioritised shared likely functional single nucleotide polymorphisms (SNPs) for allele-specific and cell type–specific functional interrogation using electromobility shift, luciferase reporter, and quantitative chromatin conformation capture assays and clustered regularly interspaced short palindromic repeat (CRISPR) gene regulation. Results: Five shared SNPs were identified as likely functional in primary human immune cells, salivary gland and kidney tissues: rs57494551, rs4936443, rs4938572, rs7117261, and rs4938573. All 5 SNPs exhibited cell type-specific and allele-specific effects on nuclear protein binding affinity and enhancer/promoter regulatory activity in immune, salivary gland epithelial, and kidney epithelial cell models. Mapping of chromatin–chromatin interactions revealed a chromatin regulatory network that expanded beyond DDX6 and CXCR5 to include PHLDB1, lnc-PHLDB1-1, BCL9L, TRAPPC4, among others. Coalescence of functional assays and multiomic data analyses indicated that these SNPs likely modulate the activity of 3 regulatory regions: intronic rs57494551 regulatory region, intergenic SNP haplotype (rs4938572, rs4936443, and rs7117261) regulatory region, and rs4938573 regulatory region upstream of the CXCR5 promoter. Conclusions: Shared genetic susceptibly at the DDX6-CXCR5 locus in SjD and SLE likely alters common mechanisms of autoimmunity, including interferon signalling (DDX6), autophagy (TRAPPC4), and lymphocytic infiltration of disease-target tissues (CXCR5). Further, using multiomic data from patients with SjD, combined with bioinformatic and in vitro functional studies, can provide mechanistic insights into how genetic risk influences the ...
Document Type: article in journal/newspaper
File Description: application/pdf
Language: English
Relation: Annals of the Rheumatic Diseases, 0003-4967, 2025, 84:9, s. 1512-1527; PMID 40447495; ISI:001570633500008
DOI: 10.1016/j.ard.2025.04.023
Availability: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-239821; https://doi.org/10.1016/j.ard.2025.04.023
Rights: info:eu-repo/semantics/openAccess
Accession Number: edsbas.C93F6043
Database: BASE