Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity.

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 STE 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.