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Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

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 and Baecklund, Eva , et al. (2023) In bioRxiv : the preprint server for biology p.1-48
Abstract

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic 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 on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1.... (More)

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic 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 on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-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 of DDX6, CXCR5, and lnc-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.

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organization
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type
Working paper/Preprint
publication status
published
subject
in
bioRxiv : the preprint server for biology
pages
1 - 48
publisher
bioRxiv
external identifiers
  • pmid:39071447
ISSN
2692-8205
DOI
10.1101/2023.10.05.561076
language
English
LU publication?
yes
id
11b4320d-8116-4d7b-be05-b98adfa05dab
date added to LUP
2025-01-23 12:31:39
date last changed
2025-05-20 09:42:11
@misc{11b4320d-8116-4d7b-be05-b98adfa05dab,
  abstract     = {{<p>Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic 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 on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-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 of DDX6, CXCR5, and lnc-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.</p>}},
  author       = {{Wiley, Mandi M and Khatri, Bhuwan and Joachims, Michelle L and Tessneer, Kandice L and Stolarczyk, Anna M and Rasmussen, Astrid and Anaya, Juan-Manuel and Aqrawi, Lara A and Bae, Sang-Cheol and Baecklund, Eva and Björk, Albin and Brun, Johan G and Bucher, Sara Magnusson and Dand, Nick and Eloranta, Maija-Leena and Engelke, Fiona and Forsblad-d'Elia, Helena and Fugmann, Cecilia and Glenn, Stuart B and Gong, Chen and Gottenberg, Jacques-Eric and Hammenfors, Daniel and Imgenberg-Kreuz, Juliana and Jensen, Janicke Liaaen and Johnsen, Svein Joar Auglænd and Jonsson, Malin V and Kelly, Jennifer A and Khanam, Sharmily and Kim, Kwangwoo and Kvarnström, Marika and Mandl, Thomas and Martín, Javier and Morris, David L and Nocturne, Gaetane and Norheim, Katrine Brække and Olsson, Peter and Palm, Øyvind and Pers, Jacques-Olivier and Rhodus, Nelson L and Sjöwall, Christopher and Skarstein, Kathrine and Taylor, Kimberly E and Tombleson, Phil and Thorlacius, Gudny Ella and Venuturupalli, Swamy and Vital, Edward M and Wallace, Daniel J and Grundahl, Kiely M and Radfar, Lida and Brennan, Michael T}},
  issn         = {{2692-8205}},
  language     = {{eng}},
  month        = {{10}},
  note         = {{Preprint}},
  pages        = {{1--48}},
  publisher    = {{bioRxiv}},
  series       = {{bioRxiv : the preprint server for biology}},
  title        = {{Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland}},
  url          = {{http://dx.doi.org/10.1101/2023.10.05.561076}},
  doi          = {{10.1101/2023.10.05.561076}},
  year         = {{2023}},
}