Background/Purpose Patients with Systemic Lupus Erythematosus (SLE) have an increased risk of ischemic heart disease (IHD). Altered DNA methylation patterns have been reported both in SLE and in individuals with a history of IHD in the general population. We performed a 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 (sex 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. A linear regression model including age at sampling, blood cell type distribution and HM450k BeadChip as covariates was fitted, and association p-values were Bonferroni corrected.
Results We identified 210 differentially methylated CpG sites (DMCs) in SLE IHD, with a majority (84%) of sites showing decreased methylation levels in IHD. DMCs were annotated to 155 unique genes, of which 64% were characterized as interferon-induced. DMCs with the largest effect size were located at Complement component 4 binding protein alpha (C4BPA), Membrane spanning 4-domains A3 (MS4A3) and Triggering receptor expressed on myeloid cells 1 (TREM1). Further, a differentially methylated region with multiple DMCs was observed in the promoter region of Programmed cell death 1 gene (PDCD1), where increased methylation was associated with IHD.
Conclusion The results of this study highlight genes and mechanisms that may be implicated in the pathogenesis of and/or recovery from IHD in patients with SLE. Identified DMCs can serve as candidates for functional studies and as potential biomarkers for IHD in patients with SLE.
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