CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3ζ-chain expression in T cells.
CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3ζ-chain expression in T cells.
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CD3Z 高甲基化与系统性红斑狼疮的严重临床表现相关，并减少 T 细胞中 CD3γ 链的表达。
DOI：
10.1093/rheumatology/kew405
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Song,Yeong-Wook
中科院分区：
文献类型：
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作者：
Hong,Kyeong-Man;Kim,Hyun-Kyoung;Park,Seong-Yeol;Poojan,Shiv;Kim,Mi-Kyung;Sung,Joohon;Tsao,BettyP;Grossman,JenniferM;Rullo,OrnellaJ;Woo,JenniferMP;McCurdy,DeborahK;Rider,LisaG;Miller,FrederickW;Song,Yeong-Wook
目标。低甲基化在SLE中的重要性是公认的；然而，高甲基化的意义尚未得到很好的表征。方法：采用芯片技术在SLE全血DNA中筛选DNA甲基化标记，并通过甲基化单碱基扩展法在两个独立的种族队列（包括207例SLE患者和151例对照）中确认两个标记（CD3ZandVHLhypermethylations）。结果cd3z高甲基化和vhl高甲基化两个表观遗传标记与SLE显著相关：cd3z高甲基化（优势比为7.76,P = 1.71 × 10−13）和vhl高甲基化（优势比为3.77,P = 3.20 × 10−8），cd3z甲基化增加与SLE T细胞cd3ζ链下调相关。此外，在纵向和双胞胎样本的分析中发现，相对于vhl甲基化，cd3z甲基化的遗传影响较小。此外，较高的cd3z甲基化水平与较高的SLE疾病活动性指数和更严重的临床表现（如蛋白尿、溶血性贫血和血小板减少症）显著相关，而vhl高甲基化与此无关。cd3z高甲基化是一种SLE危险因素，可被环境因素修饰，并与更严重的SLE临床表现相关，其通过下调cd3ζ链与T细胞功能紊乱有关。
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 (CD3ZandVHLhypermethylations) 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,CD3ZandVHLhypermethylation, were significantly correlated with SLE:CD3Zhypermethylation (odds ratio = 7.76; P = 1.71 × 10−13) andVHLhypermethylation (odds ratio = 3.77; P = 3.20 × 10−8), and the increasedCD3Zmethylation was correlated with downregulation of the CD3ζ-chain in SLE T cells. In addition, less genetic influence onCD3Zmethylation relative toVHLmethylation was found in analyses of longitudinal and twin samples. Furthermore, a higherCD3Zmethylation level was significantly correlated with a higher SLE disease activity index and more severe clinical manifestations, such as proteinuria, haemolytic anaemia and thrombocytopenia, whereasVHLhypermethylation was not.Conclusion.CD3Zhypermethylation 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.