TY - JOUR
T1 - Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland
AU - Wiley, Mandi M.
AU - Radziszewski, Marcin
AU - Khatri, Bhuwan
AU - Joachims, Michelle L.
AU - Tessneer, Kandice L.
AU - Stolarczyk, Anna M.
AU - Yao, Songyuan
AU - Li, James
AU - Pritchett-Frazee, Cherilyn
AU - Johnston, Audrey A.
AU - Rasmussen, Astrid
AU - Anaya, Juan Manuel
AU - Aqrawi, Lara A.
AU - Bae, Sang Cheol
AU - Baecklund, Eva
AU - Björk, Albin
AU - Brun, Johan G.
AU - Bucher, Sara Magnusson
AU - Dand, Nick
AU - Eloranta, Maija Leena
AU - Engelke, Fiona
AU - Forsblad-d'Elia, Helena
AU - Fugmann, Cecilia
AU - Glenn, Stuart B.
AU - Gong, Chen
AU - Gottenberg, Jacques Eric
AU - Hammenfors, Daniel
AU - Imgenberg-Kreuz, Juliana
AU - Jensen, Janicke Liaaen
AU - Johnsen, Svein Joar Auglænd
AU - Jonsson, Malin V.
AU - Kelly, Jennifer A.
AU - Khanam, Sharmily
AU - Kim, Kwangwoo
AU - Kvarnström, Marika
AU - Mandl, Thomas
AU - Martín, Javier
AU - Morris, David L.
AU - Nocturne, Gaetane
AU - Norheim, Katrine Brække
AU - Olsson, Peter
AU - Palm, Øyvind
AU - Pers, Jacques Olivier
AU - Rhodus, Nelson L.
AU - Sjöwall, Christopher
AU - Skarstein, Kathrine
AU - Taylor, Kimberly E.
AU - Tombleson, Phil
AU - Thorlacius, Gudny Ella
AU - Venuturupalli, Swamy R.
AU - Vital, Edward M.
AU - Wallace, Daniel J.
AU - Radfar, Lida
AU - Brennan, Michael T.
AU - James, Judith A.
AU - Scofield, R. Hal
AU - Gaffney, Patrick M.
AU - Criswell, Lindsey A.
AU - Jonsson, Roland
AU - Appel, Silke
AU - Eriksson, Per
AU - Bowman, Simon J.
AU - Omdal, Roald
AU - Rönnblom, Lars
AU - Warner, Blake M.
AU - Rischmueller, Maureen
AU - Witte, Torsten
AU - Farris, A. Darise
AU - Mariette, Xavier
AU - Shiboski, Caroline H.
AU - Wahren-Herlenius, Marie
AU - Alarcón-Riquelme, Marta E.
AU - Ng, Wan Fai
AU - Sivils, Kathy L.
AU - Guthridge, Joel M.
AU - Adrianto, Indra
AU - Vyse, Timothy J.
AU - Tsao, Betty P.
AU - Nordmark, Gunnel
AU - Lessard, Christopher J.
N1 - Publisher Copyright:
© 2025 The Author(s)
PY - 2025/9
Y1 - 2025/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105007095088
U2 - 10.1016/j.ard.2025.04.023
DO - 10.1016/j.ard.2025.04.023
M3 - Article
C2 - 40447495
AN - SCOPUS:105007095088
SN - 0003-4967
VL - 84
SP - 1512
EP - 1527
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 9
ER -
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