Meyer Braydon, Chavez Raul A, Munro Jane E, Chiaroni-Clarke Rachel C, Akikusa Jonathan D, Allen Roger C, Craig Jeffrey M, Ponsonby Anne-Louise, Saffery Richard, Ellis Justine A
Genes, Environment &Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
1] Genes, Environment &Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria, Australia [2] Department of Paediatrics, University of Melbourne, Victoria, Australia.
Sci Rep. 2015 Jun 9;5:11063. doi: 10.1038/srep11063.
Juvenile idiopathic arthritis (JIA) is the most common autoimmune rheumatic disease of childhood. We recently showed that DNA methylation at the gene encoding the pro-inflammatory cytokine interleukin-32 (IL32) is reduced in JIA CD4+ T cells. To extend this finding, we measured IL32 methylation in CD4+ T-cells from an additional sample of JIA cases and age- and sex-matched controls, and found a reduction in methylation associated with JIA consistent with the prior data (combined case-control dataset: 25.0% vs 37.7%, p = 0.0045). Further, JIA was associated with reduced IL32 methylation in CD8+ T cells (15.2% vs 25.5%, p = 0.034), suggesting disease-associated changes to a T cell precursor. Additionally, we measured regional SNPs, along with CD4+ T cell expression of total IL32, and the γ and β isoforms. Several SNPs were associated with methylation. Two SNPs were also associated with JIA, and we found evidence of interaction such that methylation was only associated with JIA in minor allele carriers (e.g. rs10431961 p(interaction) = 0.011). Methylation at one measured CpG was inversely correlated with total IL32 expression (Spearman r = -0.73, p = 0.0009), but this was not a JIA-associated CpG. Overall, our data further confirms that reduced IL32 methylation is associated with JIA, and that SNPs play an interactive role.
幼年特发性关节炎（JIA）是儿童期最常见的自身免疫性风湿性疾病。我们最近发现，促炎细胞因子白细胞介素-32（IL32）编码基因的DNA甲基化在JIA的CD4 + T细胞中减少。为了扩展这一发现，我们在另一组JIA病例以及年龄和性别匹配的对照样本的CD4 + T细胞中测量了IL32甲基化，发现与JIA相关的甲基化减少，这与先前的数据一致（合并病例对照数据集：25.0%对37.7%，p = 0.0045）。此外，JIA与CD8 + T细胞中IL32甲基化减少相关（15.2%对25.5%，p = 0.034），提示疾病相关的T细胞前体变化。此外，我们测量了区域单核苷酸多态性（SNP），以及总IL32、γ和β亚型在CD4 + T细胞中的表达。几个SNP与甲基化相关。两个SNP也与JIA相关，并且我们发现了相互作用的证据，即甲基化仅在次要等位基因携带者中与JIA相关（例如rs10431961，p（相互作用）= 0.011）。一个测量的CpG处的甲基化与总IL32表达呈负相关（斯皮尔曼r = -0.73，p = 0.0009），但这不是与JIA相关的CpG。总体而言，我们的数据进一步证实IL32甲基化减少与JIA相关，并且SNP起相互作用的作用。
