Genome-wide methylation profiling in Crohn's disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway
Genome-wide methylation profiling in Crohn's disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway
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DOI：
10.1002/ibd.21912
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发表时间：
2012-05-01
影响因子：
4.9
通讯作者：
Satsangi, Jack
中科院分区：
文献类型：
--
作者：
Nimmo, Elaine R.;Prendergast, James G.;Satsangi, Jack
背景资料：全基因组关联研究（GWAS）所涉及的71个克罗恩病（CD）基因座的生殖系变异仅占估计遗传力的约25%。表观遗传改变对疾病发病机制的贡献正在成为研究的重点。材料和方法：使用Illumina Human Methylation 27检测从40名成年女性（21名回肠CD，19名健康对照）和16名儿童期发病CD女孩（均为非吸烟者）的全血样本中提取的DNA，分析基因组中27，578个CpG位点的甲基化状态。我们的初步分析比较了成人病例和对照组的甲基化谱。结果：我们的数据定义了回肠CD的整体甲基化特征。总共有1117个位点发生了差异甲基化（校正后P < 0.01）;与对照组相比，病例组中有50个位点的甲基化发生了显著改变（未校正P < 10-6，校正后P < 0.0006），包括改变免疫激活的基因：MAPK 13、FASLG、PRF 1、S100 A13、RIPK 3和IL-21 R。基因本体分析表明免疫相关途径是表观遗传修饰的靶点（免疫系统过程[P = 1.3 x 10-22]、免疫应答[P = 8.1 x 10-16]、对细菌的防御应答[P = 1.8 x 10-15]）。免疫抑制经典途径分析涉及树突状细胞活性（P = 2.4 x 10-8）和白细胞介素（IL）-17 A和IL-17 F对细胞因子的差异调节（P = 5.8 x 10-7）。我们鉴定了CD GWAS基因座50 kb内甲基化变化的显著富集（成人为8.6倍[P = 0.021];成人和儿童合并为2.4倍[P = 0.009]），包括IL-27、IL-19、TNF、MST 1和NOD 2。甲基化状态是疾病状态的预测指标（敏感性0.71，特异性0.83）。疾病活动、药物治疗、NOD 2和DNMT 3A基因型与甲基化变化无关。结论：这些数据提供了一个重要的洞察力的影响，表观遗传机制的发病机制CD。（Inflamm Bowel Dis 2011;）
Background: Germline variation in the 71 Crohn's disease (CD) loci implicated by genome-wide association studies (GWAS) only accounts for approximately 25% of estimated heritability. The contribution of epigenetic alterations to disease pathogenesis is emerging as a research priority. Materials and Methods: The methylation status of 27,578 CpG sites across the genome was analyzed using the Illumina Human Methylation27 assay in DNA extracted from whole blood samples from 40 adult females (21 ileal CD, 19 healthy controls) and 16 girls with childhood-onset CD, all nonsmokers. Our primary analysis compared methylation profiles in adult cases and controls. Results: Our data define a global methylation profile characteristic of ileal CD. In all, 1117 sites were differentially methylated (corrected P < 0.01); 50 showed significantly altered methylation in cases compared with controls (uncorrected P < 10-6, corrected P < 0.0006), including genes altering immune activation: MAPK13, FASLG, PRF1, S100A13, RIPK3, and IL-21R. Gene ontology analyses implicated immunity-related pathways as targets of epigenetic modification (immune system processes [P = 1.3 x 10-22], immune response [P = 8.1 x 10-16], defense responses to bacteria [P = 1.8 x 10-15]). Ingenuity canonical pathway analyses implicated dendritic cell activity (P = 2.4 x 10-8) and differential regulation of cytokines by interleukin (IL)-17A and IL-17F (P = 5.8 x 10-7). We identified a significant enrichment of methylation changes within 50 kb of CD GWAS loci (8.6-fold [P = 0.021] in adults; 2.4-fold [P = 0.009] in adults and children combined), including IL-27, IL-19, TNF, MST1, and NOD2. Methylation status was predictive of disease status (sensitivity 0.71, specificity 0.83). Disease activity, drug therapy, NOD2 and DNMT3A genotypes were not associated with methylation changes. Conclusions: These data provide an important insight into the impact of epigenetic mechanisms in the pathogenesis of CD. (Inflamm Bowel Dis 2011;)