Gene expression and regulation in systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. Genome-wide (GW) association studies have identified more than 40 disease-associated loci, together accounting for only 10-20% of disease heritability. Gene expression represents the intermediate phenotype between DNA and disease phenotypic variation, and provides insights regarding genetic and epigenetic effects. We review data on gene expression and regulation in SLE by our group and other investigators.

Materials and methods: Systematic PubMed search for GW expression studies in SLE published since the year 2000.

Results: Deregulation of genes involved in type I interferon signaling is a consistent finding in the peripheral blood of active and severe SLE patients. Upregulation of granulocyte-specific transcripts especially in bone marrow mononuclear cells (BMMCs), and of myeloid lineage transcripts in lupus nephritis, provide evidence for pathogenic role of these cells. Gene network analysis in BMMCs identified central gene regulators which could represent therapeutic targets and a high similarity between SLE and non-Hodgkin lymphoma providing a molecular basis for the reported association of the two diseases. Gene expression abnormalities driven by deregulated expression of certain microRNAs in SLE contribute to interferon production, T- and B-cell hyperactivity, DNA hypomethylation, and defective tissue response to injury. Methylation arrays have revealed alterations in white blood cell DNA methylation in SLE suggesting an important role of epigenetics and the environment.

Conclusions: Gene expression studies have contributed to the characterization of pathogenic processes in SLE. Integrated approaches utilizing genetic variation, transcriptome and epigenome profiling will facilitate efforts towards a molecular-based disease taxonomy.