Variants in theDDX6-CXCR5autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland
Author:
Wiley Mandi M., Khatri Bhuwan, Joachims Michelle L., Tessneer Kandice L., Stolarczyk Anna M., 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 KwangwooORCID, Kvarnström Marika, Mandl Thomas, Martín Javier, Morris David L.ORCID, 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, Vital Edward M.ORCID, Wallace Daniel J, Grundahl Kiely M., 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. DariseORCID, Mariette Xavier, Shiboski Caroline H., Wahren-Herlenius Marie, Alarcón-Riquelme Marta E., Ng Wan-Fai, Sivils Kathy L., Guthridge Joel M.ORCID, Adrianto Indra, Vyse Timothy J., Tsao Betty P., Nordmark Gunnel, Lessard Christopher J.ORCID, , ,
Abstract
ABSTRACTFine mapping and bioinformatic analysis of theDDX6-CXCR5genetic risk association in Sjögren’s Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects onDDX6andCXCR5expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, includinglnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression ofDDX6,CXCR5, andlnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.
Publisher
Cold Spring Harbor Laboratory
|
|