Background/Purpose: Patients with systemic lupus erythematosus (SLE) have an increased risk of ischemic heart disease (IHD). Altered methylation patterns have been reported both in SLE, including hypomethylation of interferon (IFN) regulated genes, and in individuals with a history of IHD in the general population. We performed a matched case-case epigenome-wide association study (EWAS) for IHD in patients with SLE to identify phenotype-specific differences in DNA methylation.

Methods: DNA methylation profiles from peripheral blood samples of 33 SLE patients with a history of IHD (myocardial infarction and or angina pectoris) and 66 matched (ethnicity and age) SLE patients without any prior cardiovascular events were generated on the HumanMethylation450k array (Illumina). All patients were female, fulfilled ≥ 4 ACR-82 SLE criteria and were recruited at the Uppsala, Linköping and Karolinska University hospitals, Sweden. Association was tested using a logistic regression model including age at sampling, blood cell type distribution and HM450k BeadChip as covariates. Differentially methylated CpG sites (DMCs) were defined as p< 1.3×10-7 based on Bonferroni correction and an absolute average difference in methylation beta of |Δβ| >0.05. Functional gene-set enrichment analyses were conducted using the ToppGene Suite database and for classification of IFN regulated genes the Interferome v2.01 database was queried.

Results: We identified 210 DMCs in SLE IHD, with a majority (84.3%) of DMCs showing decreased methylation levels in IHD. The strongest differentially methylated DMCs were located at Complement component 4 binding protein alpha (C4BPA) (|Δβ|=-0.06, p=1.1×10^-13), Membrane spanning 4-domains A3 (MS4A3) (|Δβ|=-0.07, p=3.7×10^-13) and Triggering receptor expressed on myeloid cells 1 (TREM1) (|Δβ|=-0.07, p=8.7×10^-13). Further, a differentially methylated region with multiple DMCs was observed in the promoter region of Programmed cell death 1 gene (PDCD1). DMCs in SLE IHD were annotated to 155 unique genes, of which 63.9% were characterized as interferon-induced. Gene-set enrichment analysis revealed response to oxidative stress (p=1.0×10^-5), vesicle-mediated transport (p=1.1×10^-6) and inflammasomes (p=6.4×10^-6) as the most significantly enriched pathways in SLE IHD.

Conclusion: The results of this study highlight genes and pathways that may be implicated in the pathogenesis of and/or recovery from IHD in patients with SLE. The identified DMCs can serve as candidates for functional studies and as potential biomarkers for IHD in patients with SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epigenome-wide-association-study-reveals-differential-dna-methylation-in-systemic-lupus-erythematosus-patients-with-a-history-of-ischemic-heart-disease/