eQTL analysis in systemic sclerosis identifies new candidate genes associated with multiple aspects of disease pathology.

Objective To identify the genetic variants that affect gene expression (expression quantitative trait loci, eQTLs) in systemic sclerosis (SSc) to investigate their role in the pathogenesis of the disease. Methods We performed an eQTL analysis using whole blood sequencing data of 333 SSc patients and 524 controls and integrated them with SSc GWAS data. We integrated our findings from modelling of expression, differential expression analysis and transcription factor binding site (TFBS) enrichment with key clinical features of SSc. Results We detected 49,123 validated cis-eQTLs from 4,539 SSc associated SNPs (pGWAS 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 blood cells, skin, or lung tissue of SSc patients. TFBS analysis revealed enriched motifs of 24 TFs (5%) among SSc eQTLs, five of which were found to be differentially regulated in 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 two have been tested in clinical trials in patients with SSc. Conclusion The data of the present study provides a new layer of the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.