Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease. In addition to genetic and environmental influences, the discordance rate between monozygotic (MZ) twins suggests a role for epigenetic factors in disease. The analysis of MZ twins represents the ideal design to assess the role of epigenetic factors in disease etiology. Here, we report the results of a genome-wide analysis of DNA methylation on 3 MZ twin pairs discordant for SLE.
Methods: Genomic DNA was extracted from peripheral blood of 3 MZ twin pairs discordant for SLE. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip. Probes with a detection P-value<1.0E-05 were excluded. In order to identify differentially methylated genes between unaffected and affected twins, a paired t-test on the probe-specific β-values was computed and significance was assessed as the intersection of meeting an FDR threshold (1.06x10E-7) and mean DNA methylation difference (Δβ)>|0.10|.
Results: Global hypomethylation of interferon-inducible genes was observed in the affected twins. Analysis of the top loci using Gene Ontology suggested an enrichment of epigenetic changes in genes involved in response to biotic stimulus (GO:0009607; P(Benjamini)=0.0077) and response to virus (GO:0009615; P(Benjamini )=0.021), and their functional annotation using Panther revealed an enrichment of two biological processes, immunity and defense (BP00148; P(Benjamini)=0.0044) and interferon-mediated immunity (BP00156; P(Benjamini)=0.032). The top hypomethylated sites in the affecteds were located in several interferon-inducible genes, including MX1 (Δβ =-0.47, P=6.59E-13), IFI44L (Δβ =-0.29, P=1.58E-14), and IFITM1 (Δβ =-0.25, P=4.41E-40). Other significant loci included the polymerase PARP9 (P=6.74E-126, Δβ =-0.37), the cytidine kinase CMPK2 (Δβ =-0.33, P=7.98E-08), and the cyclic nucleotide phosphodiesterase PDE7A genes (Δβ =-0.35, P=1.21E-09).
Conclusion: These data support a role for DNA methylation differences in mediating susceptibility to SLE. Furthermore, these observed hypomethylation of interferon-inducible genes offers a mechanistic explanation for the well know overexpression of interferon-inducible genes observed in patients with SLE and other autoimmune diseases.
P. S. Ramos,
T. D. Howard,
M. C. Marion,
J. A. Kelly,
K. L. Moser,
C. D. Langefeld,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epigenetic-profiling-in-monozygotic-twins-discordant-for-systemic-lupus-erythematosus-reveals-prominent-hypomethylation-of-interferon-inducible-genes/