DNA甲基化異常與系統性紅斑狼瘡

系統性紅斑狼瘡(SLE)是一種慢性系統性自身免疫性疾病，傳統的遺傳學研究發現，DNA序列完全一致的同卵雙胞胎對SLE的易感性不同，其同患SLE的一致率僅為39%-60%。

這可能與DNA合成後修飾在基因表達調控中的作用相關，其中DNA甲基化異常在SLE發病中的作用越來越受到人們的關注。迄今研究已證實異常DNA甲基化通過調控一系列SLE相關基因的表達，導致SLE的發生，目前已發現的基因包括穿孔素基因、CD70、LFA-1等。最新研究結果詳見下文：

研究目的

SLE是一種慢性自身免疫性疾病，其臨床表現具有異質性，病因複雜多樣，越來越多的研究認為DNA甲基化改變參與SLE的發病。本研究分析了大量SLE患者和健康人群的DNA甲基化特徵，旨在探索發現新的SLE表觀遺傳學改變並研究其與SLE遺傳風險之間的關係。

研究方法

從548例SLE患者和587例健康對照者的血液標本中提取DNA，採用IIIumina公司生產的人甲基化450k晶元對DNA標本進行分析，該晶元可靶向整個基因組的485000個CpG位點。將來自相同個體的採用IIIumina公司生產的免疫晶元進行分析得到的196524個單核甘酸多態性基因型數據進行甲基化數量性狀位點分析。

研究結果

我們在SLE患者基因組7245個CpG位點中識別並複製了不同的甲基化CpG位點。研究發現，最大的甲基化差異出現在I型干擾素調節的基因中，這些基因在SLE患者中表現為甲基化降低。我們繪製了順式甲基化數量性狀位點圖譜並從中鑒定出SLE患者466個不同甲基化程度的CpG位點甲基化水平的遺傳調控。SLE的遺傳相關性分析豐富了採用甲基化數量性狀位點分析方法分析得到的不同甲基化CpG位點的意義，包括7個SLE全基因組關聯研究位點：PTPRC (CD45), MHC-classIII、UHRF1BP1、IRF5、IRF7、IKZF3 和 UBE2L3。此外，我們還發現SLE患者20個不同甲基化程度CpG位點的甲基化水平差異與基因型存在關聯，包括HLA-DQB2位點。

研究結論

本研究結果表明，SLE的幾種遺傳風險變異可能是通過改變靶基因調控區域的DNA甲基化水平，從而對錶型產生影響。

原 文

DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus.

Abstract

OBJECTIVES:

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.

METHODS:

DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450?k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.

RESULTS:

We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.

CONCLUSIONS:

Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

參考文獻：Ann Rheum Dis. 2018 Feb 1. pii: annrheumdis-2017-212379. doi: 10.1136/annrheumdis-2017-212379.

來源：狼瘡在線

譯者：李旭綿

喜歡這篇文章嗎？立刻分享出去讓更多人知道吧！