Background/Purpose: Systemic Lupus Erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a complex aetiology and heterogenous symptomatology which has been recently dissected using a combination of transcriptome and methylome (1). Epigenetic alterations are mediators of the environmental and genetic factors and impact transcriptional programs. Here, the aim was to increase the knowledge of epigenetic alterations in SLE by studying their link with genetics, transcription, and serological profiles in the form of cytokines and autoantibody measurements.

Methods: Whole blood DNA methylation (DNAm) data was obtained with the Illumina HumanMethylation EPIC BeadChip and coupled with genetic and RNAseq in 207 SLE patients and 235 healthy controls. We performed stratified epigenome-wide association studies interrogating the influence of the presence of autoantibodies and four distinct molecular subtypes on the epigenome. The results were followed conducting methylation quantitative trait loci analyses (meQTL), cytokine-epigenetic associations, methylation-expression correlations. The causality behind epigenetic associations was evaluated by Mendelian randomization.

Results: Despite reducing sample size, the molecular stratification approach led to a substantial increase in associated SLE-CpG sites due to patient classification within molecular subtypes, leading to a total of 974 differential methylation CpG sites. A stronger epigenetic dysregulation in interferon regulated genes (IRG) was observed in those SLE patients exhibiting SSA autoantibodies, but the interferon signature was persistent in all patients regardless their autoantibody profile. Novel genetic loci were discovered associated with SLE with evidence supporting their role as drivers of the epigenetic changes. For example, those meQTLs that regulate DNAm at IRF7 or STAT1. While the activity of transcription factors (TFs) such as IRF9, IRF1, STAT2, STAT1, E2F2 and RUNX3 was associated with the epigenetic landscape of SLE, these TFs do not have an impact on the healthy population. Likewise, strong associations between IL1RII levels and DNAm at IRG were observed with intriguing opposite directions between different SLE patient molecular subtypes.

Conclusion: This study expands the list of CpGs associated with SLE by targeting SLE molecular and autoantibody heterogeneity. The findings reveal distinct drivers for epigenetic alterations dependent on molecular subtypes, such as regulatory genetic variants, transcription factor activity or the production of inflammatory cytokines. Our work illustrates how the genetic architecture of DNAm is dependent on immunological and molecular profiles. Finally, this work serves to inspire the identification of future epigenetic biomarkers for different SLE subtypes and pinpoint new targets for drug discovery.

(1) Barturen, et al., A&R, 2021

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/consequences-of-sle-heterogeneity-on-the-epigenome-and-the-drivers-behind/