title: Ethnicity-specific epigenetic variation in naïve CD4+ T cells and the susceptibility to autoimmunity.
abstract: BACKGROUND
  Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases. T cells play an important role in several autoimmune conditions, including lupus, which is more common and more severe in people of African descent. To investigate inherent epigenetic differences in T cells between ethnicities, we characterized genome-wide DNA methylation patterns in naïve CD4+ T cells in healthy African-Americans and European-Americans, and then confirmed our findings in lupus patients.
  
  
  RESULTS
  Impressive ethnicity-specific clustering of DNA methylation profiling in naïve CD4+ T cells was revealed. Hypomethylated loci in healthy African-Americans were significantly enriched in pro-apoptotic and pro-inflammatory genes. We also found hypomethylated genes in African-Americans to be disproportionately related to autoimmune diseases including lupus. We then confirmed that these genes, such as IL32, CD226, CDKN1A, and PTPRN2 were similarly hypomethylated in lupus patients of African-American compared to European-American descent. Using patch DNA methylation and luciferase reporter constructs, we showed that methylation of the IL32 promoter region reduces gene expression in vitro. Importantly, bisulfite DNA sequencing demonstrated that cis-acting genetic variants within and directly disrupting CpG sites account for some ethnicity-specific variability in DNA methylation.
  
  
  CONCLUSIONS
  Ethnicity-specific inherited epigenetic susceptibility loci in CD4+ T cells provide clues to explain differences in the susceptibility to autoimmunity and possibly other T cell-related diseases between populations.
authors.affiliation: Division of Rheumatology, University of Michigan, 5520 MSRB-1, SPC 5680, 1150 W. Medical Center Drive, Ann Arbor, MI 48109 USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Coit
authors.affiliation: Division of Rheumatology, University of Michigan, 5520 MSRB-1, SPC 5680, 1150 W. Medical Center Drive, Ann Arbor, MI 48109 USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Ognenovski
authors.affiliation: Division of Rheumatology, University of Michigan, 5520 MSRB-1, SPC 5680, 1150 W. Medical Center Drive, Ann Arbor, MI 48109 USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gensterblum
authors.affiliation: Division of Rheumatology, Henry Ford Health System, 3031 W Grand Blvd, Detroit, MI 48202 USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Maksimowicz-McKinnon
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th St, MS 53, Oklahoma City, OK 73104 USA ; Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, 1100 N Lindsay Ave, Oklahoma City, OK 73104 USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Division of Rheumatology, University of Michigan, 5520 MSRB-1, SPC 5680, 1150 W. Medical Center Drive, Ann Arbor, MI 48109 USA ; Center for Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave, #2017, Ann Arbor, MI 48109 USA.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
keywords: Autoimmunity; Epigenetic; Ethnicity specific; Genetic; Lupus; T cell