Abstract
Systemic lupus erythematosus (SLE) is more common in women than men, but the disease is more severe when it affects men. Lupus CD4+ T cells demonstrate dysregulated DNA methylation patterns. The purpose of this study was to investigate genome-wide CD4+ T cell differential DNA methylation between men (n = 12) and women (n = 10) with SLE. DNA methylation was evaluated using the Infinium MethylationEPIC array, and differences between male versus female SLE patients were calculated with probe-wise linear regressions with adjustment for age and disease activity. We identified 198 hypomethylated and 108 hypermethylated CpG sites in CD4+ T cells isolated from male compared to female SLE patients, annotated to 201 and 102 genes, respectively. A great proportion of these genes were related to apoptosis and immune functions. Among differentially methylated genes, CASP10, which is involved in the extrinsic apoptotic pathway, and multiple genes involved in T cell function and differentiation such as ELAVL1, UHRF1, and SMAD2, were hypomethylated in men compared to women with SLE. Importantly, network analysis of differentially methylated genes revealed a pattern consistent with increased activation of ROCK, PP2A, PI3K, and ERK1/ERK2 in men compared to women with SLE. These data provide epigenetic evidence suggesting activation of key T cell pathways in men compared to women with SLE and shed new light into possible mechanisms underlying increased SLE disease severity in men.