Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren's syndrome.
Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren's syndrome.
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DOI：
10.1371/journal.pone.0248429
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Barcellos LF
中科院分区：
文献类型：
--
作者：
Chi C;Taylor KE;Quach H;Quach D;Criswell LA;Barcellos LF
免疫基因的差异甲基化是干燥综合征（SS）中在CD 4 + T细胞、CD 19 + B细胞、全血和唇唾液腺（LSG）中观察到的一致主题。多项研究发现了支持SS中DNA甲基化遗传控制的相关性，在缺乏反向因果关系的情况下，这对表观遗传治疗的潜力具有积极意义。然而，缺乏对遗传变异、DNA甲基化和疾病状态之间因果关系的正式研究。我们进行了一个因果中介分析的DNA甲基化作为一个调解员附近的遗传关联与SS使用LSG和基因型数据收集从131名女性成员的舍格伦的国际合作临床联盟注册，包括64 SS的情况下，67例非病例。首先使用Bumphunter鉴定差异甲基化区域（DMR），然后应用因果推断检验（CIT）鉴定介导邻近甲基化数量性状位点（MeQTL）与SS关联的DMR。Bumphunter发现了215个DMR，其中大部分位于染色体6p21.3上的主要组织相容性复合体（MHC）中。与以前的研究结果相一致，SS病例中低甲基化的区域富集了与免疫过程相关的基因集。使用CIT，我们总共观察到19个DMR-MeQTL对，这些对表现出强有力的证据表明存在因果中介关系。这些DMR中接近一半位于MHC中，并且它们相应的meQTL位于跨越HLA-DQA 1、HLA-DQB 1和HLA-DQA 2基因座的区域中。由MHC中这些相应的MeQTL赋予的SS风险进一步由先前的全基因组关联研究结果证实，具有独立效应的适度证据。通过验证因果中介的存在，我们的研究结果表明遗传和表观遗传因素都有助于疾病的易感性，并告知靶向表观遗传修饰作为SS治疗方法的发展。
Differential methylation of immune genes has been a consistent theme observed in Sjögren’s syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren’s International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.
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影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
27.4
作者：
Charras, Amandine;Konsta, Orsia D.;Renaudineau, Yves
通讯作者：
Renaudineau, Yves
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
12.3
作者：
Horvath S
通讯作者：
Horvath S
影响因子：
5.8
作者：
Aryee, Martin J.;Jaffe, Andrew E.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.