Murdoch Childrens Research Institute; Royal Children's Hospital; Melbourne, VIC Australia; NHMRC Centre for Food and Allergy Research; Murdoch Childrens Research Institute; Royal Children's Hospital; Melbourne, VIC Australia; Honorary Fellow University of Melbourne; Melbourne, VIC Australia.
Murdoch Childrens Research Institute; Royal Children's Hospital; Melbourne, VIC Australia.
Epigenetics. 2014 Jul;9(7):998-1006. doi: 10.4161/epi.28945. Epub 2014 Apr 24.
Food allergy is mediated by a combination of genetic and environmental risk factors, potentially mediated by epigenetic mechanisms. CD4+ T-cells are key drivers of the allergic response, and may therefore harbor epigenetic variation in association with the disease phenotype. Here we retrospectively examined genome-wide DNA methylation profiles (~450,000 CpGs) from CD4+ T-cells on a birth cohort of 12 children with IgE-mediated food allergy diagnosed at 12-months, and 12 non-allergic controls. DNA samples were available at two time points, birth and 12-months.
control comparisons of CD4+ methylation profiles identified 179 differentially methylated probes (DMP) at 12-months and 136 DMP at birth (FDR-adjusted P value<0.05, delta β>0.1). Approximately 30% of DMPs were coincident with previously annotated SNPs. A total of 92 [corrected] allergy-associated non-SNP DMPs were present at birth when individuals were initially disease-free, potentially implicating these loci in the causal pathway. Pathway analysis of differentially methylated genes identified several MAP kinase signaling molecules. Mass spectrometry was used to validate 15 CpG sites at 3 candidate genes. Combined analysis of differential methylation with gene expression profiles revealed gene expression differences at some but not all allergy associated differentially methylated genes. Thus, dysregulation of DNA methylation at MAPK signaling-associated genes during early CD4+ T-cell development may contribute to suboptimal T-lymphocyte responses in early childhood associated with the development of food allergy.
食物过敏是由遗传和环境风险因素共同介导的，可能由表观遗传机制介导。CD4+T 细胞是过敏反应的关键驱动因素，因此可能与疾病表型相关存在表观遗传变异。在这里，我们回顾性地检查了 12 名在 12 个月时被诊断为 IgE 介导的食物过敏的儿童和 12 名非过敏对照的 CD4+T 细胞的全基因组 DNA 甲基化谱（~450,000 个 CpG）。DNA 样本可在出生和 12 个月时获得两个时间点。
在 12 个月和出生时，CD4+甲基化谱的病例对照比较分别确定了 179 个差异甲基化探针（DMP）和 136 个 DMP（经 FDR 调整的 P 值<0.05，δβ>0.1）。大约 30%的 DMP 与先前注释的 SNP 重合。当个体最初无病时，总共存在 92 个[纠正]与过敏相关的非 SNP DMP，这可能暗示这些基因座参与了因果途径。差异甲基化基因的途径分析确定了几个 MAP 激酶信号分子。使用质谱法验证了 3 个候选基因的 15 个 CpG 位点。差异甲基化与基因表达谱的联合分析揭示了一些但不是所有与过敏相关的差异甲基化基因的基因表达差异。因此，在 CD4+T 细胞发育早期，MAPK 信号相关基因的 DNA 甲基化失调可能导致与食物过敏发展相关的儿童早期 T 淋巴细胞反应不佳。
