Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland
- PMID: 40447495
- PMCID: PMC12236377
- 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
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.
Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Competing interests AR received consulting fees from Immunovant and Clinical Outcomes Solutions. ND received a teaching honorarium from the British Association of Dermatologists. JLJ received travel support from the University of Oslo. MVJ received travel support from the International Symposium for Sjögren’s Syndrome 2022 and serves as a members’ representative for the Journal of the Norwegian Dental Association (Tidende). SK is currently employed at Beckman Coulter Inc. TM is currently employed by UCB Pharma. GNoc received consulting fees from Abbvie, Novartis, Galapagos, and Amgen and travel support from Amgen and UCB and is a member of the Boehringer Ingelheim Advisory Board. PO received consulting fees from UCB and Lilly and a speaker honorarium from the Internetmedicin.se (website). CS is employed as Director, CAR-T Immunology European Medical Engagement Lead, at Bristol-Myers-Squib (since April 2024); received speaker honorariums from AstraZeneca, Novartis, and Bristol-Myers Squibb; and is a member of the Fresenius Kabi Advisory Board. GET is employed by DeCODE genetics/Amgen Inc. SRV served on the American College of Rheumatology Board of Governors and has received research support from Navidea Biopharmaceuticals Inc, ARGENX, Mallinckrodt, Janssen, and Kiniksa Pharmaceuticals. EMV received research support from AstraZeneca; consulting fees from AstraZeneca, UCB, Otsuka, Abbvie, Novartis, Aurinia, and Pfizer; and payment for expert testimony from the National Institute of Health and Clinical Excellence and serves as a member of the Aurinia Data Safety and Monitoring Board, General Secretary of SLEuro, and Chair of BILAG. MTB received research support and consulting fees from Meira GTx, Lipella, and Sun Pharmaceuticals and travel support from the North Carolina Dental Society. JAJ received research support from the National Institutes of Health and Progentec Biosciences and consulting fees from GSK and Novartis. RHS is a consultant for Johnson & Johnson Innovative Medicine and Merk Pharmaceuticals, served on a clinical trial advisory board for Janssen Pharmaceuticals, and served on the IQVIA data safety and monitoring board for a clinical trial in Sjögren’s disease. SJB served on advisory boards and received consulting fees and travel support in the past 3 years from Abbvie, Amgen, Argenx, Artivabio, Aurinia, Bain, BMS, EcoR1, IQVIA, J&J, Kiniksa, Novartis, and Scitaris. LR received consulting fees and speaker honorarium form AstraZeneca. BMW has active collaborative research agreements with Astellas Bio and Pfizer Inc. MR received grants from Amgen, Argenx, AstraZeneca, Bristol Myers-Squibb, Horizon Therapeutics, Novartis, and Servier for clinical trials in Sjögren’s syndrome and SLE. TW received consulting fees from AbbVie, Boehringer Ingelheim, Fresenius Kabi, Galapagos, Janssen, Lilly, and Novartis; speaker honorariums from those listed plus Amgen, AstraZeneca, Chugai, GSK, Medac, Nordic, Sanofi, and UCB; and travel support from AbbVie, Janssen, Lilly, and UCB. ADF received research support from Johnson & Johnson Innovative Medicine (formerly Janssen; ended December 31, 2023). XM received consulting fees from BMS, GSK, Janssen, Novartis, Otsuka, and Pfizer. MEA-R has an active research collaboration with Sanofi, GSK, Novartis, Astra Zeneca, Janssen, and BMS; has received funding from Sanofi and BMS; and has received consulting fees from GSK. W-FN provided consulting services for Novartis, BMS, Janssen, Sanofi, Abbvie, IQVIA, Argenx, and Resolve Therapeutics. KLS currently employed by Johnson & Johnson Innovative Medicine. CJL received research support from Johnson & Johnson Innovative Medicine (formerly Janssen; ended December 31, 2023); consulting fees from Janssen Global Servicers, and served as a member for the Johnson and Johnson Sjögren’s Disease Advisory Board. All other authors declared no conflicts of interest.
Update of
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Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.bioRxiv [Preprint]. 2023 Oct 6:2023.10.05.561076. doi: 10.1101/2023.10.05.561076. bioRxiv. 2023. Update in: Ann Rheum Dis. 2025 May 29:S0003-4967(25)00949-5. doi: 10.1016/j.ard.2025.04.023. PMID: 39071447 Free PMC article. Updated. Preprint.
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