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Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies.

ABSTRACT: DNA methylation has emerged as an important contributing factor in the pathogenesis of systemic lupus erythematosus (SLE). Here, we describe the DNA methylation patterns identified in SLE and how these epigenetic changes can influence disease susceptibility, clinical heterogeneity, and disease flares.Several genome-wide DNA methylation studies have been recently completed in SLE. Important observations include robust demethylation of interferon-regulated genes, which is consistent across all cell types studied to date, and is independent of disease activity. This interferon epigenetic signature was shown to precede interferon transcription signature in SLE, suggesting it might be an early event in the disease process. Recent studies also revealed DNA methylation changes specific for renal and skin involvement in SLE, providing a proof of principle for a value of DNA methylation studies in exploring mechanisms of specific disease manifestations, and potentially as prognostic biomarkers. Inherited ethnicity-specific DNA methylation patterns have also been shown to possibly contribute to differences in SLE susceptibility between populations. Finally, a recent study revealed that DNA methylation levels at IFI44L can accurately distinguish SLE patients from healthy controls, and from patients with other autoimmune diseases, promising to be the first epigenetic diagnostic marker for SLE. Genome-wide DNA methylation studies in SLE have provided novel insights into disease pathogenesis, clinical heterogeneity, and disease flares. Further studies promise to reveal novel diagnostic, prognostic, and therapeutic targets for SLE.

SUBMITTER: Teruel M

PROVIDER: S-EPMC5819620 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies.

Teruel Maria M Sawalha Amr H AH

Current rheumatology reports 20170601 6

<h4>Purpose of review</h4>DNA methylation has emerged as an important contributing factor in the pathogenesis of systemic lupus erythematosus (SLE). Here, we describe the DNA methylation patterns identified in SLE and how these epigenetic changes can influence disease susceptibility, clinical heterogeneity, and disease flares.<h4>Recent findings</h4>Several genome-wide DNA methylation studies have been recently completed in SLE. Important observations include robust demethylation of interferon-r ...[more]

PMID: 28470479

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Project description:Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies associated with specific clinical manifestations. Previous studies have shown an association between differential DNA methylation and SLE susceptibility, but have not investigated SLE-related autoantibodies. Our goal was to determine whether DNA methylation is associated with production of clinically relevant SLE-related autoantibodies, with an emphasis on the anti-dsDNA autoantibody. In this study, we characterized the methylation status of 467,314 CpG sites in 326 women with SLE. Using a discovery and replication study design, we identified and replicated significant associations between anti-dsDNA autoantibody production and the methylation status of 16 CpG sites (pdiscovery<1.07E-07 and preplication<0.0029) in 11 genes. Associations were further investigated using multivariable regression to adjust for estimated leukocyte cell proportions and population substructure. The adjusted mean DNA methylation difference between anti-dsDNA positive and negative cases ranged from 1.2% to 19%, and the adjusted odds ratio for anti-dsDNA autoantibody production comparing the lowest and highest methylation tertiles ranged from 6.8 to 18.2. Differential methylation for these CpG sites was also associated with anti-SSA, anti-Sm, and anti-RNP autoantibody production. Overall, associated CpG sites were hypomethylated in autoantibody positive compared to autoantibody negative cases. Differential methylation of CpG sites within the major histocompatibility region was not strongly associated with autoantibody production. Genes with differentially methylated CpG sites represent multiple biologic pathways, and have not been associated with autoantibody production in genetic association studies. In conclusion, hypomethylation of CpG sites within genes from different pathways is associated with anti-dsDNA, anti-SSA, anti-Sm, and anti-RNP production in SLE, and these associations are not explained by genetic variation. Thus, studies of epigenetic mechanisms such as DNA methylation represent a complementary method to genetic association studies to identify biologic pathways that may contribute to the clinical heterogeneity of autoimmune diseases.

Dataset Information

Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies.

Publications

Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies.

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