Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland
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
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
Affiliation
Oklahoma Medical Research Foundation; University of Oklahoma; Universidad de la Costa; Kristiania University College; University of Oslo; Hanyang University Hospital; Hanyang University; Uppsala University; Karolinska Institutet; Haukeland University Hospital; University of Bergen; Örebro University; King's College London; Hannover Medical School; University of Gothenburg; Umeå Universitet; Hôspitaux Universitaires de Strasbourg; Université de Strasbourg; Institut National de la Santé et de la Recherche Médicale Strasbourg; Stavanger University Hospital; Kyung Hee University; Stockholm Health Services; Skane University Hospital Malmö; Lund University; Instituto de Parasitología y Biomedicina López-Neyra; Université Paris-Saclay; Assistance Publique - Hôpitaux de Paris; Oslo University Hospital; University of Brest; Centre Hospitalier Universitaire de Brest; University of Minnesota; Linköping University; University of California San Francisco; Cedars-Sinai Medical Center; University of Leeds; Leeds Teaching Hospital NHS Trust; Atrium Health Carolinas Medical Center; Wake Forest University; US Department of Veteran Affairs Medical Center; National Institutes of Health Bethesda; University Hospitals Birmingham NHS Foundation Trust; National Institute of Dental and Craniofacial Research Bethesda; Queen Elizabeth Hospital Adelaide; University of Adelaide; University of Granada; Newcastle upon Tyne Hospitals NHS Foundation Trust; Newcastle University; University College Cork; Henry Ford Health; Michigan State University; Medical University of South Carolina
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Publication date
2025-05-30
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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.
Citation
Wiley MM, Radziszewski M, Khatri B, Joachims ML, Tessneer KL, Stolarczyk AM, Yao S, Li J, Pritchett-Frazee C, Johnston AA, Rasmussen A, Anaya JM, Aqrawi LA, Bae SC, Baecklund E, Björk A, Brun JG, Bucher SM, Dand N, Eloranta ML, Engelke F, Forsblad-d'Elia H, Fugmann C, Glenn SB, Gong C, Gottenberg JE, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kelly JA, Khanam S, Kim K, Kvarnström M, Mandl T, Martín J, Morris DL, Nocturne G, Norheim KB, Olsson P, Palm Ø, Pers JO, Rhodus NL, Sjöwall C, Skarstein K, Taylor KE, Tombleson P, Thorlacius GE, Venuturupalli SR, Vital EM, Wallace DJ, Radfar L, Brennan MT, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Appel S, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner BM, Rischmueller M, Witte T, Farris AD, Mariette X, Shiboski CH; Sjögren’s International Collaborative Clinical Alliance (SICCA); Wahren-Herlenius M, Alarcón-Riquelme ME; PRECISESADS Clinical Consortium; Ng WF; UK Primary Sjögren’s Syndrome Registry; Sivils KL, Guthridge JM, Adrianto I, Vyse TJ, Tsao BP, Nordmark G, Lessard CJ. Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland. Ann Rheum Dis. 2025 Sep;84(9):1512-1527. doi: 10.1016/j.ard.2025.04.023. Epub 2025 May 30.
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Article