Purpose Systemic Lupus Erythematosus is a prototypic systemic autoimmune disease characterized by a complex aetiology and heterogeneous symptomatology. Epigenetic alterations are mediators of environmental and genetic factors and impact transcriptional programs. We aim to increase the knowledge of the contribution of epigenetics to SLE heterogeneity by studying its link with molecular subtypes, serological profiles, genetics and transcription, and use these data for drug discovery.

Methods Whole blood DNA methylation obtained with the Illumina HumanMethylation EPIC BeadChip was coupled with genetic and RNA sequencing data based on 213 SLE patients and 221 healthy controls from PRECISESADS. We performed epigenome wide association studies in a stratified fashion. We followed up results by conducting methylation quantitative loci analyses, cytokine-epigenetic associations, methylation-transcription factor activity correlations and the identification of new potential drug targets.

Results Differential methylation was observed at 974 CpG sites across the genome, many of them associated with SLE with dependence on the molecular subtypes and to a less extent to autoantibody profile. We discovered novel genetic loci associated with SLE that might exert their risk through DNA methylation changes, and a group of genetic variants that regulate DNA methylation in certain immunological or molecular contexts. Epigenetic associations with cytokine production and transcription factor activity also exhibit a high degree of specificity.

Conclusions This study expands the list of CpGs associated with SLE, with its heterogeneity revealing the pathways involved as well as the role of genetics regulating epigenetic signals, the influence of transcription factors shaping epigenomic landscapes and a group of cytokines that might be released as a consequence of epigenetic changes. This works discovers putative novel targets for drug discovery and biomarkers.