Background Patients with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD), including ischemic heart disease (IHD). 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 in peripheral blood samples from two independent cohorts of Swedish SLE patients (n=347 and n=201, respectively) was assayed on the HumanMethylation450k BeadChip array, targeting 485,000 CpG sites across the genome. Clinical data were retrieved from medical charts and individuals with a history of CVD were identified in both cohorts. Differential DNA methylation between SLE patients with a history of IHD (n=20 and n=17, respectively) and SLE patients without any CVD events prior to DNA sampling was tested using a logistic regression model including age, sex and cell type distribution as covariates. Differentially methylated CpG sites in the discovery cohort were defined as p<1.3E-7 for association based on Bonferroni correction and an absolute average difference in methylation beta of ||>0.05. Significance in the replication cohort was determined as p<0.05 and same direction of effect.
Results The top associated differentially methylated CpG sites that were replicated were identified at programmed cell death 1 (PDCD1, p(disc)=3.2E-13; p(repl)=0.03), perforin 1 (PRF1, p(disc)=1E-12; p(repl)=0.03) and ZFP36 ring finger protein like 1 (ZFP36L1, p(disc)=1.3E-11; p(repl)=0.002), all of which are implicated in apoptotic processes. Functional pathway analysis of genes containing sites with altered methylation in SLE IHD pointed to muscle contraction (p=4.3E-10), cardiac conduction (p=2.2E-7) and role of agrin in postsynaptic differentiation (p=2.9E-7) as the most significantly enriched pathways.
Conclusions 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 differentially methylated CpG sites identified in this study can serve as candidates for further evaluation by functional studies and as potential biomarkers for IHD in patients with SLE.
Funding Source(s): None
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