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

Ann Rheum Dis. 2019 Aug;78(8):1079-1089. doi: 10.1136/annrheumdis-2018-214379. Epub 2019 Jun 5.


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.

Keywords: autoimmunity; disease activity; systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Disease Progression
  • Female
  • Gene Expression Profiling / methods*
  • Genetic Predisposition to Disease / epidemiology*
  • Genetic Variation
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Interferon Type I / genetics*
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology*
  • Male
  • Middle Aged
  • Phenotype
  • RNA, Messenger / genetics
  • Reference Values
  • Transcriptome / genetics
  • Young Adult


  • Interferon Type I
  • RNA, Messenger