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Lookup NU author(s): Professor Fai Ng
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2025 The Author(s). 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.
Author(s): Wiley MM, Radziszewski M, Khatri B, Joachims ML, Tessneer KL, Stolarczyk AM, Yao S, Li J, Pritchett-Frazee C, Johnston AA, Rasmussen A, Anaya J-M, Aqrawi LA, Bae S-C, Baecklund E, Bjork A, Brun JG, Bucher SM, Dand N, Eloranta M-L, Engelke F, Forsblad-d'Elia H, Fugmann C, Glenn SB, Gong C, Gottenberg J-E, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kelly JA, Khanam S, Kim K, Kvarnstrom M, Mandl T, Martin J, Morris DL, Nocturne G, Norheim KB, Olsson P, Palm O, Pers J-O, Rhodus NL, Sjowall 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, Ronnblom L, Warner BM, Rischmueller M, Witte T, Farris AD, Mariette X, Shiboski CH, Wahren-Herlenius M, Alarcon-Riquelme ME, Ng W-F, Sivils KL, Guthridge JM, Adrianto I, Vyse TJ, Tsao BP, Nordmark G, Lessard CJ
Publication type: Article
Publication status: Published
Journal: Annals of the Rheumatic Diseases
Year: 2025
Volume: 84
Issue: 9
Pages: 1512-1527
Print publication date: 01/09/2025
Online publication date: 30/05/2025
Acceptance date: 22/04/2025
Date deposited: 16/06/2025
ISSN (print): 0003-4967
ISSN (electronic): 1468-2060
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.ard.2025.04.023
DOI: 10.1016/j.ard.2025.04.023
Data Access Statement: SjD genome-wide association summary statistics and individual-level data used in SjD-DS1 are previously reported and available through the Databases of Genotypes and Phenotypes (dbGaP) under accession number: phs002723.v1.p1 (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs002723.v1.p1), phs000672.v1.p1 (n=735) (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000672.v1.p1), phs000428.v2.p2 (n=8,519) (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000428.v2.p2), phs000196.v3.p1 (n=995) (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000196.v3.p1), and phs000187.v1.p1 (n=602) (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000187.v1.p1). SLE Immunochip and GWAS data used in SLE-DS2, previously reported, are available from the corresponding authors of the original articles in accordance with respective institutional review board approval and subject consent.
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