title: CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3ζ-chain expression in T cells.
abstract: The importance of hypomethylation in SLE is well recognized; however, the significance of hypermethylation has not been well characterized. We screened hypermethylated marks in SLE and investigated their possible implications.
  
  
  
  DNA methylation marks were screened in SLE whole-blood DNA by microarray, and two marks ( CD3Z and VHL hypermethylations) were confirmed by a methylation single-base extension method in two independent ethnic cohorts consisting of 207 SLE patients and 151 controls. The correlation with clinical manifestations and the genetic influence on those epigenetic marks were analysed.
  
  
  
  Two epigenetic marks, CD3Z and VHL hypermethylation, were significantly correlated with SLE: CD3Z hypermethylation (odds ratio = 7.76; P = 1.71 × 10 -13 ) and VHL hypermethylation (odds ratio = 3.77; P = 3.20 × 10 -8 ), and the increased CD3Z methylation was correlated with downregulation of the CD3ζ-chain in SLE T cells. In addition, less genetic influence on CD3Z methylation relative to VHL methylation was found in analyses of longitudinal and twin samples. Furthermore, a higher CD3Z methylation level was significantly correlated with a higher SLE disease activity index and more severe clinical manifestations, such as proteinuria, haemolytic anaemia and thrombocytopenia, whereas VHL hypermethylation was not.
  
  
  
  CD3Z hypermethylation is an SLE risk factor that can be modified by environmental factors and is associated with more severe SLE clinical manifestations, which are related to deranged T cell function by downregulating the CD3ζ-chain.
authors.affiliation: Research Institute, National Cancer Center, Goyang.
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Hong
authors.affiliation: Research Institute, National Cancer Center, Goyang.
authors.forename: Hyun-Kyoung
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Research Institute, National Cancer Center, Goyang.
authors.forename: Seong-Yeol
authors.initials: SY
authors.lastname: Park
authors.affiliation: Research Institute, National Cancer Center, Goyang.
authors.forename: Shiv
authors.initials: S
authors.lastname: Poojan
authors.affiliation: Research Institute, National Cancer Center, Goyang.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea.
authors.forename: Joohon
authors.initials: J
authors.lastname: Sung
authors.affiliation: Department of Medicine-Rheumatology.
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Department of Medicine-Rheumatology.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Grossman
authors.affiliation: Division of Pediatric Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Ornella J
authors.initials: OJ
authors.lastname: Rullo
authors.affiliation: Division of Pediatric Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Jennifer M P
authors.initials: JM
authors.lastname: Woo
authors.affiliation: Division of Pediatric Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: McCurdy
authors.affiliation: Department of Health and Human Services, Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Rider
authors.affiliation: Department of Health and Human Services, Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Miller
authors.affiliation: Department of Internal Medicine.|Department of Molecular Medicine and Biopharmaceutical Sciences, Medical Research Center, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Yeong-Wook
authors.initials: YW
authors.lastname: Song
mesh_terms: D000328:Adult; D017252:CD3 Complex / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D056910:Republic of Korea; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014481:United States; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: CD3Z hypermethylation; environmental factor; systemic lupus erythematosus