DNA Methylation and Gene Expression Changes in Monozygotic Twins Discordant for Psoriasis: Identification of Epigenetically Dysregulated Genes

Monozygotic (MZ) twins do not show complete concordance for many complex diseases; for example, discordance rates for autoimmune diseases are 20%–80%. MZ discordance indicates a role for epigenetic or environmental factors in disease. We used MZ twins discordant for psoriasis to search for genome-wide differences in DNA methylation and gene expression in CD4+ and CD8+ cells using Illumina's HumanMethylation27 and HT-12 expression assays, respectively. Analysis of these data revealed no differentially methylated or expressed genes between co-twins when analyzed separately, although we observed a substantial amount of small differences. However, combined analysis of DNA methylation and gene expression identified genes where differences in DNA methylation between unaffected and affected twins were correlated with differences in gene expression. Several of the top-ranked genes according to significance of the correlation in CD4+ cells are known to be associated with psoriasis. Further, gene ontology (GO) analysis revealed enrichment of biological processes associated with the immune response and clustering of genes in a biological pathway comprising cytokines and chemokines. These data suggest that DNA methylation is involved in an epigenetic dysregulation of biological pathways involved in the pathogenesis of psoriasis. This is the first study based on data from MZ twins discordant for psoriasis to detect epigenetic alterations that potentially contribute to development of the disease.

同卵双生（Monozygotic, MZ）双胞胎在多种复杂疾病中并未表现出完全一致的发病一致性；以自身免疫性疾病为例，其发病不一致率可达20%~80%。同卵双生子的发病不一致性提示表观遗传或环境因素在疾病发生过程中发挥关键作用。本研究选取银屑病发病不一致的同卵双生子队列，分别借助Illumina公司的HumanMethylation27甲基化芯片与HT-12基因表达检测平台，对CD4+和CD8+细胞中的全基因组DNA甲基化与基因表达差异进行系统性筛选。对上述数据进行单独分析后发现，尽管我们观察到大量细微的分子差异，但双胞胎共生子之间并未检测到差异甲基化基因或差异表达基因。然而，联合分析DNA甲基化与基因表达数据后，我们鉴定出一批基因，其患病与未患病双胞胎间的DNA甲基化差异与基因表达差异呈显著相关。在CD4+细胞中，依据相关性显著性排名靠前的数个核心基因，已被证实与银屑病发病相关。进一步的基因本体论（Gene Ontology, GO）分析显示，与免疫应答相关的生物学过程显著富集，且相关基因在细胞因子与趋化因子构成的生物学通路中呈现聚集特征。上述数据表明，DNA甲基化参与了银屑病发病机制中相关生物学通路的表观遗传失调。本研究是首个基于银屑病发病不一致的同卵双生子数据，探索潜在参与疾病发生发展的表观遗传改变的学术研究。