Murdoch Children's Research Institute, Parkville, Vic 3052, Australia; Department of Paediatrics, The University of Melbourne, Vic 3010, Australia.
Murdoch Children's Research Institute, Parkville, Vic 3052, Australia; Department of Paediatrics, The University of Melbourne, Vic 3010, Australia; In-FLAME, the International Inflammation Network, World Universities Network (WUN), Australia.
J Autoimmun. 2018 Jan;86:29-38. doi: 10.1016/j.jaut.2017.09.010. Epub 2017 Sep 29.
Juvenile idiopathic arthritis (JIA) is presumed to be driven by an adverse combination of genes and environment. Epigenetic processes, including DNA methylation, act as a conduit through which the environment can regulate gene activity. Altered DNA methylation has been associated with adult autoimmune rheumatic diseases such as rheumatoid arthritis, but studies are lacking for paediatric autoimmune rheumatic diseases including JIA. Here, we performed a genome-scale case-control analysis of CD4 T cell DNA methylation from 56 oligoarticular JIA (oJIA) cases and 57 age and sex matched controls using Illumina HumanMethylation450 arrays. DNA methylation at each array probe was tested for association with oJIA using RUV (Remove Unwanted Variation) together with a moderated t-test. Further to this 'all-inclusive' analysis, we stratified by age at diagnosis (≤6yrs, >6yrs) and by sex as potential sources of heterogeneity. Following False Discovery Rate (FDR) adjustment, no probes were associated with oJIA in the all-inclusive, >6yrs-diagnosed, or sex-stratified analyses, and only one probe was associated with oJIA in the ≤6yrs-diagnosed analysis. We attempted technical validation and replication of 14 probes (p<0.01) at genes of known/potential relevance to disease. At VPS53, we demonstrated a regional shift towards higher methylation in oJIA (all-inclusive) compared to controls. At REEP3, where polymorphism has been previously associated with JIA, we demonstrated higher DNA methylation in male oJIA compared to male controls. This is the most comprehensive JIA case-control analysis of DNA methylation to date. While we have generated some evidence of altered methylation in oJIA, substantial differences are not apparent in CD4 T cells. This may indicate a lesser relevance of DNA methylation levels in childhood, compared to adult, rheumatic disease.
幼年特发性关节炎（JIA）被认为是由基因和环境的不利组合驱动的。表观遗传过程，包括 DNA 甲基化，作为环境调节基因活性的途径。DNA 甲基化的改变与成人自身免疫性风湿病如类风湿关节炎有关，但对于包括 JIA 在内的儿科自身免疫性风湿病的研究尚缺乏。在这里，我们使用 Illumina HumanMethylation450 阵列对 56 例寡关节炎 JIA（oJIA）病例和 57 名年龄和性别匹配的对照者的 CD4 T 细胞 DNA 甲基化进行了全基因组病例对照分析。使用 RUV（去除不必要的变异）和经过修正的 t 检验，测试了每个阵列探针的 DNA 甲基化与 oJIA 的相关性。在这项“包罗万象”的分析之外，我们还根据诊断时的年龄（≤6 岁，>6 岁）和性别进行分层，作为潜在的异质性来源。在经过错误发现率（FDR）调整后，在包罗万象的、>6 岁诊断的或性别分层的分析中，没有探针与 oJIA 相关，只有一个探针与≤6 岁诊断的分析相关。我们尝试了 14 个探针（p<0.01）的技术验证和复制，这些探针与疾病的已知/潜在相关基因有关。在 VPS53 中，我们在 oJIA（包罗万象）中与对照组相比，观察到向更高甲基化的区域转移。在 REEP3 中，先前已证明其多态性与 JIA 相关，我们发现男性 oJIA 中的 DNA 甲基化高于男性对照组。这是迄今为止最全面的 JIA 病例对照 DNA 甲基化分析。虽然我们已经产生了一些 oJIA 中改变的甲基化的证据，但在 CD4 T 细胞中并没有明显的差异。这可能表明与成人风湿性疾病相比，儿童的 DNA 甲基化水平相关性较小。
