Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity. Issue 8 (5th August 2019)

• Record Type: Journal Article
• Authors: Panousis, Nikolaos I; Bertsias, George K; Ongen, Halit; Gergianaki, Irini; Tektonidou, Maria G; Trachana, Maria; Romano-Palumbo, Luciana; Bielser, Deborah; Howald, Cedric; Pamfil, Cristina; Fanouriakis, Antonis; Kosmara, Despoina; Repa, Argyro; Sidiropoulos, Prodromos; Dermitzakis, Emmanouil T; Boumpas, Dimitrios T
• Is Part Of: Annals of the rheumatic diseases. Volume 78:Issue 8(2019)
• Page Start: 1079
• Publication Date: 2019-08-05
• Subjects: autoimmunity -- disease activity -- systemic lupus erythematosus; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-214379
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: Systemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the molecular basis for its heterogeneity elusive. We explored the genomic basis for disease susceptibility and severity. Methods: mRNA sequencing and genotyping in blood from 142 patients with SLE and 58 healthy volunteers. Abundances of cell types were assessed by CIBERSORT and cell-specific effects by interaction terms in linear models. Differentially expressed genes (DEGs) were used to train classifiers (linear discriminant analysis) of SLE versus healthy individuals in 80% of the dataset and were validated in the remaining 20% running 1000 iterations. Transcriptome/genotypes were integrated by expression-quantitative trail loci (eQTL) analysis; tissue-specific genetic causality was assessed by regulatory trait concordance (RTC). Results: SLE has a 'susceptibility signature' present in patients in clinical remission, an 'activity signature' linked to genes that regulate immune cell metabolism, protein synthesis and proliferation, and a 'severity signature' best illustrated in active nephritis, enriched in druggable granulocyte and plasmablast/plasma–cell pathways. Patients with SLE have also perturbed mRNA splicing enriched in immune system and interferon signalling genes. A novel transcriptome index distinguished active versus inactive disease—but not low disease activity—and correlated with disease severity. DEGs discriminate SLE versus healthy individuals with median sensitivity 86% and specificity 92% suggesting a potential use in diagnostics. Combined eQTL analysis from the Genotype Tissue Expression (GTEx) project and SLE-associated genetic polymorphisms demonstrates that susceptibility variants may regulate gene expression in the blood but also in other tissues. Conclusion: Specific gene networks confer susceptibility to SLE, activity and severity, and may facilitate personalised care.