Expression Quantitative Trait Locus Analysis in Systemic Sclerosis Identifies New Candidate Genes Associated With Multiple Aspects of Disease Pathology. Issue 7 (28th May 2021)

• Record Type: Journal Article
• Authors: Kerick, Martin; González‐Serna, David; Carnero‐Montoro, Elena; Teruel, Maria; Acosta‐Herrera, Marialbert; Makowska, Zuzanna; Buttgereit, Anne; Babaei, Sepideh; Barturen, Guillermo; López‐Isac, Elena; Lesche, Ralf; Beretta, Lorenzo; Alarcon‐Riquelme, Marta E.; Martin, Javier
• Other Names: Vigone Barbara investigator.; Pers Jacques‐Olivier investigator.; Saraux Alain investigator.; Devauchelle‐Pensec Valérie investigator.; Cornec Divi investigator.; Jousse‐Joulin Sandrine investigator.; Lauwerys Bernard investigator.; Ducreux Julie investigator.; Maudoux Anne‐Lise investigator.; Vasconcelos Carlos investigator.; Tavares Ana investigator.; Neves Esmeralda investigator.; Faria Raquel investigator.; Brandão Mariana investigator.; Campar Ana investigator.; Marinho António investigator.; Farinha Fátima investigator.; Almeida Isabel investigator.; Mantecón Miguel Angel Gonzalez‐Gay investigator.; Alonso Ricardo Blanco investigator.; Martínez Alfonso Corrales investigator.; Cervera Ricard investigator.; Rodríguez‐Pintó Ignasi investigator.; Espinosa Gerard investigator.; Lories Rik investigator.; De Langhe Ellen investigator.; Hunzelmann Nicolas investigator.; Belz Doreen investigator.; Witte Torsten investigator.; Baerlecken Niklas investigator.; Stummvoll Georg investigator.; Zauner Michael investigator.; Lehner Michaela investigator.; Collantes Eduardo investigator.; Ortega‐Castro Rafaela investigator.; Aguirre‐Zamorano Mª Angeles investigator.; Escudero‐Contreras Alejandro investigator.; Castro‐Villegas Mª Carmen investigator.; Ortego Norberto investigator.; Roldán María Concepción Fernández investigator.; Raya Enrique investigator.; Moleón Inmaculada Jiménez investigator.; de Ramon Enrique investigator.; Quintero Isabel Díaz investigator.; Meroni Pier Luigi investigator.; Gerosa Maria investigator.; Schioppo Tommaso investigator.; Artusi Carolina investigator.; Chizzolini Carlo investigator.; Zuber Aleksandra investigator.; Wynar Donatienne investigator.; Kovács Laszló investigator.; Balog Attila investigator.; Deák Magdolna investigator.; Bocskai Márta investigator.; Dulic Sonja investigator.; Kádár Gabriella investigator.; Hiepe Falk investigator.; Gerl Velia investigator.; Thiel Silvia investigator.; Maresca Manuel Rodriguez investigator.; López‐Berrio Antonio investigator.; Aguilar‐Quesada Rocío investigator.; Navarro‐Linares Héctor investigator.;
• Is Part Of: Arthritis & rheumatology. Volume 73:Issue 7(2021)
• Page Start: 1288
• Page End: 1300
• Publication Date: 2021-05-28
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.41657
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: To identify the genetic variants that affect gene expression (expression quantitative trait loci [eQTLs]) in systemic sclerosis (SSc) and to investigate their role in the pathogenesis of the disease. Methods: We performed an eQTL analysis using whole‐blood sequencing data from 333 SSc patients and 524 controls and integrated them with SSc genome‐wide association study (GWAS) data. We integrated our findings from expression modeling, differential expression analysis, and transcription factor binding site enrichment with key clinical features of SSc. Results: We detected 49, 123 validated cis ‐eQTLs from 4, 539 SSc‐associated single‐nucleotide polymorphisms (SNPs) ( P GWAS < 10 −5 ). A total of 1, 436 genes were within 1 Mb of the 4, 539 SSc‐associated SNPs. Of those 1, 436 genes, 565 were detected as having ≥1 eQTL with an SSc‐associated SNP. We developed a strategy to prioritize disease‐associated genes based on their expression variance explained by SSc eQTLs (r 2 > 0.05). As a result, 233 candidates were identified, 134 (58%) of them associated with hallmarks of SSc and 105 (45%) of them differentially expressed in the blood cells, skin, or lung tissue of SSc patients. Transcription factor binding site analysis revealed enriched motifs of 24 transcription factors (5%) among SSc eQTLs, 5 of which were found to be differentially regulated in the blood cells ( ELF1 and MGA ), skin ( KLF4 and ID4 ), and lungs ( TBX4 ) of SSc patients. Ten candidate genes (4%) can be targeted by approved medications for immune‐mediated diseases, of which only 3 have been tested in clinical trials in patients with SSc. Conclusion: The findings of the present study indicate a new layer to the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.