Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.
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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, Sjögren’s International Collaborative Clinical Alliance (SICCA), Wahren-Herlenius Marie, Alarcón-Riquelme Marta E, PRECISESADS Clinical Consortium, Ng Wan-Fai, UK Primary Sjögren’s Syndrome Registry, Sivils Kathy L, Guthridge Joel M, Adrianto Indra, Vyse Timothy J, Tsao Betty P, Nordmark Gunnel, Lessard Christopher J
Аннотация
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.