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

Academic Article

Abstract

  • © 2019, American College of Rheumatology Objective: To 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. Methods: B 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. Results: Regression 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. Conclusion: These 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.
  • Digital Object Identifier (doi)

    Author List

  • Breitbach ME; Ramaker RC; Roberts K; Kimberly RP; Absher D
  • Start Page

  • 282
  • End Page

  • 291
  • Volume

  • 72
  • Issue

  • 2