Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland
Year: 2025
Type: article
Abstract: 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 biological pathways that drive complex autoimmunity.
Source: Annals of the Rheumatic Diseases
Authors: Mandi M. Wiley, Marcin Radziszewski, Bhuwan Khatri, Michelle L. Joachims, Kandice L. Tessneer, Anna M. Stolarczyk, Songyuan Yao, James Li, Cherilyn Pritchett-Frazee, Audrey A. Johnston, Astrid Rasmussen, Juan-Manuel Anaya, Lara A. Aqrawi, Sang-Cheol Bae, Eva Baecklund, Albin Björk, Johan G. Brun, Sara Magnusson Bucher, Nick Dand, Maija-Leena Eloranta, Fiona Engelke, Helena Forsblad-d’Elia, Cecilia Fugmann, Stuart B. Glenn, Chen Gong, Jacques-Eric Gottenberg, Daniel Hammenfors, Juliana Imgenberg-Kreuz, Janicke Liaaen Jensen, Svein Joar Auglænd Johnsen, Malin V. Jonsson, Jennifer A. Kelly, Sharmily Khanam, Kwangwoo Kim, Marika Kvarnström, Thomas Mandl, Javier Martín, David L. Morris, Gaetane Nocturne, Katrine Brække Norheim, Peter Olsson, Øyvind Palm, Jacques-Olivier Pers, Nelson L. Rhodus, Christopher Sjöwall, Kathrine Skarstein, Kimberly E. Taylor, Phil Tombleson, Gudny Ella Thorlacius, Swamy R. Venuturupalli, Edward M. Vital, Daniel J. Wallace, Lida Radfar, Michael T. Brennan, Judith A. James, R. Hal Scofield, Patrick M. Gaffney, Lindsey A. Criswell, Roland Jonsson, Silke Appel, Per Eriksson, Simon J Bowman, Roald Omdal, Lars Rönnblom, Blake M. Warner, Maureen Rischmueller, Torsten Witte, A. Darise Farris, Xavier Mariette, Caroline H Shiboski, Marie Wahren-Herlenius, Marta E. Alarcón-Riquelme, Wan-Fai Ng, Kathy L. Sivils, Joel M. Guthridge, Indra Adrianto, Timothy J. Vyse, Betty P. Tsao, Gunnel Nordmark, Christopher J. Lessard
Institutions: Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, University of the Coast, University of Oslo, Høyskolen Kristiania, Hanyang University Seoul Hospital, Hanyang University Hospital for Rheumatic Disease, Uppsala University, Karolinska Institutet, Haukeland University Hospital, University of Bergen, Örebro University, King's College London, Medizinische Hochschule Hannover, University of Gothenburg, Umeå University, Inserm, Regenerative NanoMedicine, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Stavanger University Hospital, Kyung Hee University, Stockholm Health Care Services, Lund University, Skåne University Hospital, Consejo Superior de Investigaciones Científicas, Instituto de Parasitología y Biomedicina "López - Neyra", Université Paris-Saclay, Assistance Publique – Hôpitaux de Paris, Bicêtre Hospital, Oslo University Hospital, Université de Bretagne Occidentale, University of Minnesota, Linköping University, University of California, San Francisco, Cedars-Sinai Medical Center, University of Leeds, Leeds Teaching Hospitals NHS Trust, Carolinas Medical Center, Wake Forest University Health Sciences, Wake Forest University, United States Department of Veterans Affairs, National Institutes of Health, National Human Genome Research Institute, University Hospitals Birmingham NHS Foundation Trust, National Institute of Dental and Craniofacial Research, Queen Elizabeth Hospital, The University of Adelaide, Universidad de Granada, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research, University College Cork, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne Hospital, NIHR Newcastle Biomedical Research Centre, Newcastle University, Henry Ford Health, Henry Ford Health + Michigan State University Health Sciences, Michigan State University, Medical University of South Carolina
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,870
Funders: Presbyterian Health Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Torsten Söderbergs Stiftelse, University of Washington, Johns Hopkins University, Sjögren's Foundation, National Institute for Health and Care Research, Deutsche Forschungsgemeinschaft, Assistance Publique - Hôpitaux de Paris, Cancerfonden, Knut och Alice Wallenbergs Stiftelse, Helse Vest, Stockholms Läns Landsting, Vetenskapsrådet, Norges Forskningsråd, Ministère des Affaires Sociales, de la Santé et des Droits des Femmes, Uppsala Universitet, Svenska Läkaresällskapet, Stiftelsen Konung Gustaf V:s 80-årsfond, Reumatikerförbundet, European League Against Rheumatism, Science for Life Laboratory, National Institutes of Health, NIHR Newcastle Biomedical Research Centre, Birmingham Biomedical Research Centre, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, Office of Research on Women's Health, NHLBI Division of Intramural Research
Awards: G1110106231, G1532842915, G1548716237, G173303992, G1750838956, G1982683670, G2077504343, G2144852167, G2146332128, G2157974190, G2157991818, G2197716730, G2251582088, G2265115783, G2404662676, M D Anderson Cancer Center Head & Neck SPORE, G2835605846, G2888765041, G2977898157, Molecular Epidemiology of DNA Repair in Head and Neck Cancer, G3204657967, G3226771441, G3490618080, Sjögren's International Collaborative Clinical Alliance Next Generation Studies (SICCA-NextGen), G4027718214, G4084381199, G4205375868, G421072293, G4219154071, G4389504228, G4407350458, EXC 2155: RESIST Resolving Infection Susceptibility, G457330776, Genome Wide Association Coordinating Center, G4808091200, G4871996218, G4882479958, G500259116, G5186833673, G562779432, G5684951146, International Research Registry Network for Sjogren's Syndrome, G6097850780, G6589694607, G6858459297, G6862617662, G7093047072, G7560939899, G8266053885, G8267674335, G837080710, G8558332596, G859169766, G8749809609, G9000003311, G9000084929, G9000095940, G9000165958, G9000194098, G9000218458, G9000247246, G9000263555, G9000329164, G9000337797, Oklahoma Rheumatic Disease Research Cores Center, RESOURCE-BASED CENTER FOR THE ADVANCEMENT OF PRECISION MEDICINE IN RHEUMATOLOGY, The University of Texas M. D. Anderson Cancer Center SPORE in Melanoma
OpenAlex ID: W4410907295