Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.
Mandi M WileyBhuwan KhatriMichelle L JoachimsKandice L TessneerAnna M StolarczykAstrid RasmussenJuan-Manuel AnayaLara A AqrawiSang-Cheol BaeEva BaecklundAlbin BjörkJohan G BrunSara Magnusson BucherNick DandMaija-Leena ElorantaFiona EngelkeHelena Forsblad-d'EliaCecilia FugmannStuart B GlennChen GongJacques-Eric GottenbergDaniel HammenforsJuliana Imgenberg-KreuzJanicke Liaaen JensenSvein Joar Auglænd JohnsenMalin V JonssonJennifer A KellySharmily KhanamKwangwoo KimMarika KvarnströmThomas MandlJavier MartínDavid L MorrisGaetane NocturneKatrine Brække NorheimPeter OlssonØyvind PalmJacques-Olivier PersNelson L RhodusChristopher SjöwallKathrine SkarsteinKimberly E TaylorPhil TomblesonGudny Ella ThorlaciusSwamy VenuturupalliEdward M VitalDaniel J WallaceKiely M GrundahlLida RadfarMichael T BrennanJudith A JamesR Hal ScofieldPatrick M GaffneyLindsey A CriswellRoland JonssonSilke AppelPer ErikssonSimon J BowmanRoald OmdalLars RönnblomBlake M WarnerMaureen RischmuellerTorsten WitteAmy Darise FarrisXavier MarietteCaroline H Shiboskinull nullMarie Wahren-HerleniusMarta E Alarcón-Riquelmenull nullWan-Fai Ngnull nullKathy L SivilsJoel M GuthridgeIndra AdriantoTimothy J VyseBetty P TsaoGunnel NordmarkChristopher J LessardPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- genome wide
- transcription factor
- dna methylation
- systemic lupus erythematosus
- gene expression
- binding protein
- copy number
- dna binding
- dna damage
- poor prognosis
- disease activity
- single cell
- genome wide identification
- high resolution
- small molecule
- cell migration
- air pollution
- high density
- rheumatoid arthritis
- stem cells
- cell therapy
- long non coding rna
- oxidative stress
- mass spectrometry
- bone marrow
- amino acid