Table 7_Differential DNA methylation patterns in whole blood from ACPA-positive patients with DMARD-naïve rheumatoid arthritis at clinical disease onset.xlsx

ObjectiveEpigenetic DNA imprints are increasingly being recognized as co-drivers of disease in complex conditions. In this exploratory and hypothesis-generating epigenome-wide association study (EWAS), we investigated differential methylation patterns in peripheral blood leucocytes from patients with early untreated ACPA-positive rheumatoid arthritis (RA) versus controls.
MethodsWhole blood DNA was isolated from 101 disease-modifying anti-rheumatic drug (DMARD)-naïve patients with recent clinical onset of ACPA-positive RA and 200 controls. DNA methylation was studied using the Illumina MethylationEPIC BeadChips (Illumina). We assessed our findings against previously reported differentially methylated DNA positions associated with RA including an EWAS on peripheral blood leucocytes from a similar Drop Nordic cohort.
ResultsWe identified 16,583 CpG sites and 14 differentially methylated regions (DMRs) associated with RA. The most robust DMRs were in the gene body of LAMP1 and the TNSF14 GENE known as LIGHT. We identified three novel Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, the taste transduction pathway, the olfactory pathway, and the viral carcinogenesis pathway, which have not previously been associated with RA. We replicated 2,248 CpG sites reported earlier in an EWAS on peripheral blood leukocytes from RA patients of Scandinavian ancestry with incipient untreated ACPA-positive disease.
ConclusionWe have detected a considerable number of epigenetic marks with potential relevance to the pathogenesis of RA. These findings may pave the way for the development of narrowly targeted new drugs and possibly assist to retrieve persons at particular risk of acquiring RA.

目的：表观遗传DNA印记在复杂疾病中作为疾病共同驱动因素的地位日益得到认可。本项探索性且兼具假说生成性质的全表观基因组关联研究（epigenome-wide association study, EWAS）中，我们针对抗瓜氨酸化蛋白抗体（anti-citrullinated protein antibody, ACPA）阳性的早期未治疗类风湿关节炎（rheumatoid arthritis, RA）患者与健康对照者的外周血白细胞差异甲基化模式展开了研究。
方法：本研究从101例近期临床发病且未接受过改善病情抗风湿药（disease-modifying anti-rheumatic drug, DMARD）治疗的ACPA阳性RA患者，以及200例健康对照者中分离全血DNA。采用Illumina MethylationEPIC微珠芯片（Illumina）进行DNA甲基化检测。我们将本次研究结果与既往报道的RA相关差异甲基化DNA位点进行了比对，其中包括一项针对类似的Drop Nordic队列外周血白细胞的EWAS研究。
结果：本研究共鉴定出16583个CpG位点（CpG site）以及14个差异甲基化区域（differentially methylated region, DMR）与RA相关。其中效应最为显著的DMR位于LAMP1基因编码区以及被称为LIGHT的TNSF14基因区域。我们还发现了3个此前未被报道与RA相关的全新京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路：味觉转导通路、嗅觉通路以及病毒致癌通路。此外，我们成功复现了既往一项针对斯堪的纳维亚血统的早期未治疗ACPA阳性RA患者外周血白细胞的EWAS研究中报道的2248个CpG位点。
结论：本研究检测到大量与RA发病机制潜在相关的表观遗传标记。上述研究结果可为靶向性新型药物的开发提供思路，或可辅助识别RA发病高风险人群。