Publication

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.
Author
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
Rasmussen, Astrid
Anaya, Juan-Manuel
Aqrawi, Lara A
Bae, Sang-Cheol
Baecklund, Eva
Björk, Albin
Brun, Johan G
Bucher, Sara Magnusson
Dand, Nick
Eloranta, Maija-Leena
Engelke, Fiona
Forsblad-d'Elia, Helena
Fugmann, Cecilia
Glenn, Stuart B
Gong, Chen
Gottenberg, Jacques-Eric
Hammenfors, Daniel
Imgenberg-Kreuz, Juliana
Jensen, Janicke Liaaen
Johnsen, Svein Joar Auglænd
Jonsson, Malin V
Kelly, Jennifer A
Khanam, Sharmily
Kim, Kwangwoo
Kvarnström, Marika
Mandl, Thomas
Martín, Javier
Morris, David L
Nocturne, Gaetane
Norheim, Katrine Brække
Olsson, Peter
Palm, Øyvind
Pers, Jacques-Olivier
Rhodus, Nelson L
Sjöwall, Christopher
Skarstein, Kathrine
Taylor, Kimberly E
Tombleson, Phil
Thorlacius, Gudny Ella
Venuturupalli, Swamy R
Vital, Edward M
Wallace, Daniel J
Radfar, Lida
Brennan, Michael T
James, Judith A
Scofield, R Hal
Gaffney, Patrick M
Criswell, Lindsey A
Jonsson, Roland
Appel, Silke
Eriksson, Per
Bowman, Simon J
Omdal, Roald
Rönnblom, Lars
Warner, Blake M
Rischmueller, Maureen
Witte, Torsten
Farris, A Darise
Mariette, Xavier
Shiboski, Caroline H
Wahren-Herlenius, Marie
Alarcón-Riquelme, Marta E
Ng, Wan-Fai
Sivils, Kathy L
Guthridge, Joel M
Adrianto, Indra
Vyse, Timothy J
Tsao, Betty P
Nordmark, Gunnel
Lessard, Christopher J
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Date
2025-05-30
Type
Article
Subject
Lupus erythematosus, systemic, Sjogren's syndrome, Autoimmunity, Genes, Rheumatology
Collections
UHB Genomic Medicine
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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.
Journal / Source Title
Annals of the Rheumatic Diseases
DOI
10.1016/j.ard.2025.04.023
URI
https://mider.dspace7.openrepository.com/handle/20.500.14200/8909
PMID
40447495
Publisher
Elsevier
Publisher’s URL
https://ard.bmj.com/
https://www.sciencedirect.com/journal/annals-of-the-rheumatic-diseases
Publisher’s statement
Note / Copyright