Population‐Specific Patterns of Epigenetic Defects in the B Cell Lineage in Patients With Systemic Lupus Erythematosus

Abstract

ObjectiveTo determine the stage of B cell development at which a systemic lupus erythematosus (SLE)–associated DNA methylation signature originates in African American (AA) and European American (EA) subjects, and to assess whether epigenetic defects in B cell development patterns could be predictive of SLE status in individual and mixed immune cell populations.MethodsB cells from AA patients (n = 31) and EA patients (n = 49) with or without SLE were sorted using fluorescence‐activated cell sorting into 5 B cell subsets. DNA methylation, measured at ~460,000 CpG sites, was interrogated in each subset. Enrichment analysis of transcription factor interaction at SLE‐associated methylation sites was performed. A random forests algorithm was used to identify an epigenetic signature of SLE in the B cell subsets, which was then validated in an independent cohort of AA and EA patients and healthy controls.ResultsRegression analysis across all B cell stages resulted in identification of 60 CpGs that reached genome‐wide significance for SLE‐associated methylation differences (P ≤ 1.07 × 10−7). Interrogation of ethnicity‐specific CpGs associated with SLE revealed a hypomethylated pattern that was enriched for interferon (IFN)–regulated genes and binding of EBF1 in AA patients (each P < 0.001). AA patients with SLE could be distinguished from healthy controls when the predictive model developed with the transitional B cell subset was applied to other B cell subsets (mean receiver operating characteristic [ROC] area under the curve [AUC] 0.98), and when applied to CD19+ pan–B cells (mean ROC AUC 0.95) and CD4+ pan–T cells (mean ROC AUC 0.97) from the independent validation cohort.ConclusionThese results indicate that SLE‐specific methylation patterns are ethnicity dependent. A pattern of epigenetic changes near IFN‐regulated genes early in B cell development is a hallmark of SLE in AA female subjects. EBF1 binding sites are highly enriched for significant methylation changes, implying that this may be a potential regulator of SLE‐associated epigenetic changes.