Abstract
BackgroundEpigenetic variants have been shown in recent studies to be important contributors to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report a 2-step study of discovery followed by replication to identify DNA methylation alterations associated with SLE in a Chinese population. Using a genome-wide DNA methylation microarray, the Illumina Infinium HumanMethylation450 BeadChip, we compared the methylation levels of CpG sites in DNA extracted from white blood cells from 12 female Chinese SLE patients and 10 healthy female controls.ResultsWe identified 36 CpG sites with differential loss of DNA methylation and 8 CpG sites with differential gain of DNA methylation, representing 25 genes and 7 genes, respectively. Surprisingly, 42% of the hypomethylated CpG sites were located in CpG shores, which indicated the functional importance of the loss of DNA methylation. Microarray results were replicated in another cohort of 100 SLE patients and 100 healthy controls by performing bisulfite pyrosequencing of four hypomethylated genes, MX1, IFI44L, NLRC5 and PLSCR1. In addition, loss of DNA methylation in these genes was associated with an increase in mRNA expression. Gene ontology analysis revealed that the hypomethylated genes identified in the microarray study were overrepresented in the type I interferon pathway, which has long been implicated in the pathogenesis of SLE.ConclusionOur epigenetic findings further support the importance of the type I interferon pathway in SLE pathogenesis. Moreover, we showed that the DNA methylation signatures of SLE can be defined in unfractionated white blood cells.
Highlights
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with significant morbidity and mortality
Our epigenetic findings further support the importance of the type I interferon pathway in systemic lupus erythematosus (SLE) pathogenesis
The DNA methylation levels of three different CpG sites overlapping long interspersed nucleotide element-1 (LINE-1) were investigated, and there was no significant difference between the average methylation levels of LINE-1 in controls and SLE patients (p = 0.848, Fig 1)
Summary
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with significant morbidity and mortality. Genome-wide association studies have shown that the development of SLE is associated with variants in multiple genes, such as PXK, ITGAM, CD80 and CDKN1B [5,6,7]. Methylation of CpG sites in the promoter region usually causes gene silencing [12]. Epigenetic variants have been shown in recent studies to be important contributors to the pathogenesis of systemic lupus erythematosus (SLE). We report a 2-step study of discovery followed by replication to identify DNA methylation alterations associated with SLE in a Chinese population. Using a genome-wide DNA methylation microarray, the Illumina Infinium HumanMethylation450 BeadChip, we compared the methylation levels of CpG sites in DNA extracted from white blood cells from 12 female Chinese SLE patients and 10 healthy female controls
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