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

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; Sjögren’s International Collaborative Clinical Alliance (SICCA); Marie Wahren-Herlenius; Marta E Alarcón-Riquelme; PRECISESADS Clinical Consortium; Wan-Fai Ng; UK Primary Sjögren’s Syndrome Registry; Kathy L Sivils; Joel M Guthridge; Indra Adrianto; Timothy J Vyse; Betty P Tsao; Gunnel Nordmark; Christopher J Lessard

doi:10.1016/j.ard.2025.04.023

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

Ann Rheum Dis. 2025 May 29:S0003-4967(25)00949-5. doi: 10.1016/j.ard.2025.04.023. Online ahead of print.

Authors

Mandi M Wiley¹, Marcin Radziszewski², Bhuwan Khatri¹, Michelle L Joachims³, Kandice L Tessneer¹, Anna M Stolarczyk¹, Songyuan Yao¹, James Li², Cherilyn Pritchett-Frazee¹, Audrey A Johnston⁴, Astrid Rasmussen¹, Juan-Manuel Anaya⁵, Lara A Aqrawi⁶, Sang-Cheol Bae⁷, Eva Baecklund⁸, Albin Björk⁹, Johan G Brun¹⁰, Sara Magnusson Bucher¹¹, Nick Dand¹², Maija-Leena Eloranta⁸, Fiona Engelke¹³, Helena Forsblad-d'Elia¹⁴, Cecilia Fugmann⁸, Stuart B Glenn¹, Chen Gong¹², Jacques-Eric Gottenberg¹⁵, Daniel Hammenfors¹⁰, Juliana Imgenberg-Kreuz⁸, Janicke Liaaen Jensen¹⁶, Svein Joar Auglænd Johnsen¹⁷, Malin V Jonsson¹⁸, Jennifer A Kelly¹, Sharmily Khanam⁴, Kwangwoo Kim¹⁹, Marika Kvarnström²⁰, Thomas Mandl²¹, Javier Martín²², David L Morris¹², Gaetane Nocturne²³, Katrine Brække Norheim²⁴, Peter Olsson²¹, Øyvind Palm²⁵, Jacques-Olivier Pers²⁶, Nelson L Rhodus²⁷, Christopher Sjöwall²⁸, Kathrine Skarstein¹⁰, Kimberly E Taylor²⁹, Phil Tombleson³⁰, Gudny Ella Thorlacius⁹, Swamy R Venuturupalli³¹, Edward M Vital³², Daniel J Wallace³¹, Lida Radfar³³, Michael T Brennan³⁴, Judith A James³⁵, R Hal Scofield³⁶, Patrick M Gaffney², Lindsey A Criswell³⁷, Roland Jonsson¹⁸, Silke Appel¹⁸, Per Eriksson²⁸, Simon J Bowman³⁸, Roald Omdal²⁴, Lars Rönnblom⁸, Blake M Warner³⁹, Maureen Rischmueller⁴⁰, Torsten Witte¹³, A Darise Farris³⁵, Xavier Mariette²³, Caroline H Shiboski²⁹; Sjögren’s International Collaborative Clinical Alliance (SICCA); Marie Wahren-Herlenius⁴¹, Marta E Alarcón-Riquelme⁴²; PRECISESADS Clinical Consortium; Wan-Fai Ng⁴³; UK Primary Sjögren’s Syndrome Registry; Kathy L Sivils⁴, Joel M Guthridge³⁵, Indra Adrianto⁴⁴, Timothy J Vyse¹², Betty P Tsao⁴⁵, Gunnel Nordmark⁸, Christopher J Lessard⁴⁶

Affiliations

¹ Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, USA.
² Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, USA; University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
³ Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, USA; Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, OK, USA.
⁴ Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, OK, USA.
⁵ Universidad de la Costa, Barranquilla, Colombia.
⁶ Kristiania University College, Oslo, Norway; University of Oslo, Oslo, Norway.
⁷ Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology Research and Hanyang Institute of Bioscience and Biotechnology, Seoul, Republic of Korea.
⁸ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁹ Karolinska Institutet, Stockholm, Sweden.
¹⁰ Haukeland University Hospital, Bergen, Norway; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
¹¹ Örebro University, Örebro, Sweden.
¹² Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK.
¹³ Hannover Medical School, Hannover, Germany.
¹⁴ University of Gothenburg, Gothenburg, Sweden; Umeå Universitet, Umeå, Sweden.
¹⁵ 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.
¹⁶ University of Oslo, Oslo, Norway.
¹⁷ Stavanger University Hospital, Stavanger, Norway.
¹⁸ Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
¹⁹ Kyung Hee University, Seoul, Republic of Korea.
²⁰ Karolinska Institutet, Stockholm, Sweden; Academic Specialist Center, Center for Rheumatology, Stockholm Health Services, Stockholm, Sweden.
²¹ Skane University Hospital Malmö, Lund University, Malmö, Sweden.
²² Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.
²³ Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France; Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France.
²⁴ Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway; Stavanger University Hospital, Stavanger, Norway.
²⁵ Oslo University Hospital, Oslo, Norway.
²⁶ LBAI, UMR1227, University of Brest, INSERM, Brest, France; CHU de Brest, Brest, France.
²⁷ University of Minnesota, Minneapolis, MN, USA.
²⁸ Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, Sweden.
²⁹ University of California San Francisco, San Francisco, CA, USA.
³⁰ Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK; NIHR GSTFT/KCL Biomedical Research Centre, London, UK.
³¹ Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³² Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK; NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospital NHS Trust, Leeds, UK.
³³ College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁴ Atrium Health Carolinas Medical Center, Charlotte, NC, USA; Wake Forest University School of Medicine, Winston-Salem, NC, USA.
³⁵ University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, OK, USA.
³⁶ University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, OK, USA; US Department of Veteran Affairs Medical Center, Oklahoma City, OK, USA.
³⁷ University of California San Francisco, San Francisco, CA, USA; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
³⁸ University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
³⁹ Salivary Disorders Unit and NIDCR Sjögren's Disease Clinic, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA.
⁴⁰ The Queen Elizabeth Hospital and Medical School, University of Adelaide, SA, Australia.
⁴¹ Karolinska Institutet, Stockholm, Sweden; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
⁴² Karolinska Institutet, Stockholm, Sweden; GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
⁴³ NIHR Newcastle Biomedical Research Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK; University College Cork, Cork, Ireland.
⁴⁴ Henry Ford Health, Detroit, MI, USA; Michigan State University, East Lansing, MI, USA; Henry Ford Health + Michigan State University Health Sciences, East Lansing, MI, USA.
⁴⁵ Medical University of South Carolina, Charleston, SC, USA.
⁴⁶ Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, USA; University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. Electronic address: chris-lessard@omrf.org.

PMID: 40447495
DOI: 10.1016/j.ard.2025.04.023

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.