Svendsen Anders J, Gervin Kristina, Lyle Robert, Christiansen Lene, Kyvik Kirsten, Junker Peter, Nielsen Christian, Houen Gunnar, Tan Qihua
The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark , Odense , Denmark.
Department of Medical Genetics, Oslo University Hospital, University of Oslo , Oslo , Norway.
Front Immunol. 2016 Nov 17;7:510. doi: 10.3389/fimmu.2016.00510. eCollection 2016.
In an explorative epigenome-wide association study (EWAS) to search for gene independent, differentially methylated DNA positions and regions (DMRs) associated with rheumatoid arthritis (RA) by studying monozygotic (MZ) twin pairs discordant for RA.
Genomic DNA was isolated from whole blood samples from 28 MZ twin pairs discordant for RA. DNA methylation was measured using the HumanMethylation450 BeadChips. Smoking, anti-cyclic citrullinated peptide antibodies, and immunosuppressive treatment were included as covariates. Pathway analysis was performed using GREAT.
Smoking was significantly associated with hypomethylation of a DMR overlapping the promoter region of the and the , which are implicated in inflammation and autoimmunity, whereas DMARD treatment induced hypermethylation of the same region. Additionally, the promotor region of both and were hypomethylated, and both genes have previously been associated with RA. We replicated several candidate genes identified in a previous EWAS in treatment-naïve RA singletons. Gene-set analysis indicated the involvement of immunologic signatures and cancer-related pathways in RA.
We identified several differentially methylated regions associated with RA, which may represent environmental effects or consequences of the disease and plausible biological pathways pertinent to the pathogenesis of RA.
在一项探索性全表观基因组关联研究（EWAS）中，通过研究患类风湿性关节炎（RA）的单卵（MZ）双胞胎对，寻找与RA相关的基因独立、差异甲基化的DNA位点和区域（DMR）。
从28对患RA的MZ双胞胎对的全血样本中分离基因组DNA。使用HumanMethylation450 BeadChips测量DNA甲基化。将吸烟、抗环瓜氨酸肽抗体和免疫抑制治疗作为协变量。使用GREAT进行通路分析。
吸烟与一个与炎症和自身免疫相关的DMR的低甲基化显著相关，该DMR与 和 的启动子区域重叠，而疾病改善抗风湿药物（DMARD）治疗诱导该区域的高甲基化。此外， 和 的启动子区域均为低甲基化，且这两个基因此前均与RA相关。我们在未经治疗的RA单例中重复了先前EWAS中鉴定的几个候选基因。基因集分析表明免疫特征和癌症相关通路参与了RA。
我们鉴定了几个与RA相关的差异甲基化区域，这些区域可能代表环境影响或疾病后果以及与RA发病机制相关的合理生物学通路。
