title: DNA methylation patterns in naïve CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by heterogeneous clinical manifestations, autoantibody production and epigenetic dysregulation in T cells. We sought to investigate the epigenetic contribution to the development of cutaneous manifestations in SLE.
  
  
  METHODS
  We performed genome-wide DNA methylation analyses in patients with SLE stratified by a history of malar rash, discoid rash or neither cutaneous manifestation, and age, sex and ethnicity matched healthy controls. We characterised differentially methylated regions (DMRs) in naïve CD4+ T cells unique to each disease subset, and assessed functional relationships between DMRs using bioinformatic approaches.
  
  
  RESULTS
  We identified 36 and 37 unique DMRs that contribute to the epigenetic susceptibility to malar rash and discoid rash, respectively. These DMRs were primarily localised to genes mediating cell proliferation and apoptosis. Hypomethylation of MIR886 and TRIM69, and hypermethylation of RNF39 were specific to patients with SLE with a history of malar rash. Hypomethylation of the cytoskeleton-related gene RHOJ was specific to patients with SLE with a history of discoid rash. In addition, discoid rash-specific hypomethylated DMRs were found in genes involved in antigen-processing and presentation such as TAP1 and PSMB8. Network analyses showed that DMRs in patients with SLE with but not without a history of cutaneous manifestations are associated with TAP-dependent processing and major histocompatibility-class I antigen cross-presentation (p=3.66×10(-18) in malar rash, and 3.67×10(-13) in discoid rash).
  
  
  CONCLUSIONS
  We characterised DNA methylation changes in naïve CD4+ T cells specific to malar rash and discoid rash in patients with SLE. These data suggest unique epigenetic susceptibility loci that predispose to or are associated with the development of cutaneous manifestations in SLE.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , University of Michigan , Ann Arbor, Michigan , USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Renauer
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , University of Michigan , Ann Arbor, Michigan , USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Coit
authors.affiliation: Department of Internal Medicine , University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma , USA.
authors.forename: Matlock A
authors.initials: MA
authors.lastname: Jeffries
authors.affiliation: Clinical Pharmacology Program , Oklahoma Medical Research Foundation , Oklahoma City, Oklahoma , USA.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , University of Michigan , Ann Arbor, Michigan , USA.
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: McCune
authors.affiliation: Division of Rheumatology , Henry Ford Health System , Detroit, Michigan , USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Maksimowicz-McKinnon
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , University of Michigan , Ann Arbor, Michigan , USA ; Center for Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, Michigan , USA.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
keywords: Autoimmune Diseases; Gene Polymorphism; Systemic Lupus Erythematosus