DNA methylation signature in monozygotic twins discordant for psoriatic disease [methylation array]

Psoriatic disease is a multifactorial inflammatory condition spanning from skin and nail psoriasis (Pso) to spine and joint involvement characterizing psoriatic arthritis (PsA). Monozygotic twins provide a model to investigate genetic, early life environmental exposure and stochastic influences to complex diseases, mainly mediated by epigenetics. We performed a genome-wide DNA methylation study on whole blood of monozygotic twins from 7 pairs discordant for Pso/PsA using the Infinium Methylation EPIC array (Illumina). MeDiP – qPCR was used to confirm specific signals. Data were replicated in an independent cohort of 7 patients with Pso/PsA and 3 healthy controls. We identified 2,564 differentially methylated positions between psoriatic disease and controls, corresponding to 1,703 genes, 59% within gene bodies. There were 19 regions with at least two DMPs within 1 kb of distance and significant within-pair Δβ-values (p<0.005), among them SNX25, BRG1 and SMAD3 genes, all involved in TGF-β signaling pathway, were identified. Co-expression analyses on transcriptome data identified IL-6/JAK/STAT3 and TNF-alpha pathways as important signaling axes involved in the disease, and they also suggested an altered glucose metabolism in patients’ immune cells, characteristic of pro-inflammatory T lymphocytes. The study suggests the presence of an epigenetic signature in affected individuals, pointing to genes involved in immunological and inflammatory responses. This result is also supported by transcriptome data, that altogether suggest a higher activation state of the immune system, that could promote the disease status. Genome wide DNA methylation profiling of monozygotic twins discordant for psoriatic disease. The Illumina EPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 800,000 CpGs in blood cell samples. Samples included 7 twin pairs.

银屑病疾病（Psoriatic disease）是一类多因素炎症性疾病，涵盖皮肤与指甲银屑病（psoriasis, Pso），以及表现为脊柱和关节受累的银屑病关节炎（psoriatic arthritis, PsA）。单卵双胞胎（monozygotic twins）是研究复杂疾病遗传、早期环境暴露及随机影响因素的理想模型，此类影响主要由表观遗传学（epigenetics）介导。本研究采用Infinium甲基化EPIC芯片（Illumina），对7对银屑病/银屑病关节炎表型不一致的单卵双胞胎的全血样本开展全基因组DNA甲基化分析；利用MeDiP-qPCR技术对特定信号进行验证，并在包含7名银屑病/银屑病关节炎患者与3名健康对照的独立队列中完成数据重复验证。
本研究共鉴定出2564个银屑病疾病与健康对照间的差异甲基化位点（differentially methylated positions, DMPs），对应1703个基因，其中59%的位点位于基因本体（gene bodies）内。共发现19个区域，在1kb范围内至少包含2个差异甲基化位点且具有显著的配对内Δβ值（p<0.005），其中涉及SNX25、BRG1与SMAD3基因，上述基因均参与转化生长因子-β（TGF-β, transforming growth factor-β）信号通路。对转录组（transcriptome）数据的共表达分析显示，IL-6/JAK/STAT3与肿瘤坏死因子-α（TNF-α, tumor necrosis factor-α）通路是参与该病的关键信号轴；同时研究还提示患者免疫细胞存在葡萄糖代谢异常，这一特征与促炎性T淋巴细胞的表现一致。
本研究表明受累个体存在表观遗传特征，其指向参与免疫与炎症反应的相关基因。该结论也得到转录组数据的支持，二者共同提示免疫系统处于更高激活状态，这可能促进疾病的发生发展。本数据集为银屑病疾病表型不一致的单卵双胞胎的全基因组DNA甲基化谱：研究使用Illumina EPIC人类DNA甲基化微珠芯片，获取血细胞样本中约80万个CpG位点的DNA甲基化谱，样本共包含7对双胞胎。