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- Title
CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3ς-chain expression in T cells.
- Authors
Kyeong-Man Hong; Hyun-Kyoung Kim; Seong-Yeol Park; Shiv Poojan; Mi-Kyung Kim; Joohon Sung; Tsao, Betty P.; Grossman, Jennifer M.; Rullo, Ornella J.; Woo, Jennifer M. P.; McCurdy, Deborah K.; Rider, Lisa G.; Miller, Frederick W.; Yeong-Wook Song
- Abstract
Objective. 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. Methods. 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. Results. Two epigenetic marks, CD3Z and VHL hypermethylation, were significantly correlated with SLE: CD3Z hypermethylation (odds ratio = 7.76; P = 1.71 x 10-13) and VHL hypermethylation (odds ratio = 3.77; P = 3.20 x10-8), and the increased CD3Z methylation was correlated with downregulation of the CD3ς-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. Conclusion. 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 CD3ς-chain.
- Subjects
STATISTICAL correlation; ETHNIC groups; GENE therapy; HEART; PROTEINURIA; RESEARCH funding; SYSTEMIC lupus erythematosus; T cells; T-test (Statistics); THROMBOCYTOPENIA; TWINS; LOGISTIC regression analysis; DNA methylation; EPIGENOMICS; ODDS ratio; MANN Whitney U Test; SYMPTOMS
- Publication
Rheumatology, 2017, Vol 56, Issue 3, p467
- ISSN
1462-0324
- Publication type
Article
- DOI
10.1093/rheumatology/kew405