Systemic Lupus Erythemathosus (SLE) is a prototypic systemic autoimmune disease characterized by a complex aetiology and heterogenous symptomatology. Epigenetics alterations are known to be mediators of the environmental and genetic factors and to impact transcriptional programs. Here, we aim to increase the knowledge of epigenetic alterations in SLE by conducting an epigenome-wide association study in more than 750,000 CpG sites, and by studying their link with genetics, transcription, sex and serological profiles in data from PRECISESADs project.
DNA methylation data with the Illumina HumanMethylation EPIC BeadChip derived couple with imputed genetic data and RNAseq based 207 SLE patients and 235 healthy controls from PRECISESADS was analysed. We performed an epigenome wide association study in stratified analyses that interrogated the influence of the presence of autoantibodies, the molecular profiles and the sex on the epigenetic associations. We followed up results by conducting methylation quantitative loci analyses (meQTL), cytokine-epigenetic associations and methylation-expression correlations.
Differential methylation was observed at 1200 CpG sites across the genome associated with molecular subtypes of SLE, and in relation with autoantibodies profiles and sex. We discovered novel genetic loci associated with SLE that might exert their risk through DNA methylation changes. We also identified novel meQTL specific to certain immunological contexts.
This study expands the list of CpGs associated with SLE heterogeneity and pathways invovled in SLE. Our findings reveal novel genetic risk variants with regulatory role associated SLE, novel disease-specific meQTLs, and discovers novel biomarkers for different subtypes of SLE as well as new targets for drug discovery.