Region- and variance-based DNA methylation analyses reveal novel disease genes and pathways for systemic lupus erythematosus

Background Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with unclear pathogenesis. DNA methylation is an important regulatory mechanism on gene expression, providing a key angle to understand disease mechanisms. To understand the pathways involved in SLE, and to develop biomarkers for its diagnosis and treatment, we analyzed DNA methylation profiles on blood cells from SLE patients and healthy controls. Results We identified most differentially methylated regions (DMRs) in T cells, while majority of differentially variable sites (DVSs) were found in B cells, featuring hypervariability in enhancers. We observed a prominent T cell receptor (TCR) signaling cluster with consistent hypermethylation and a B cell receptor (BCR) cluster with highly increased variability in SLE. Genes involved in innate immunity were often found hypomethylated, while adaptive immunity genes were featured with hypermethylation. Using a machine learning approach, we identified 60 genes that accurately distinguished SLE patients from healthy individuals, which also showed correlation with disease activities. Conclusions This study highlights the role of lymphocyte receptor aberrations in the disease and identified a list of genes showing great potential as biomarkers and shedding new light on disease mechanisms, through novel analyses of methylation data.