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Integrative analysis identifies potential causal methylation-mRNA regulation chains for rheumatoid arthritis
Molecular Immunology ( IF 3.6 ) Pub Date : 2020-12-30 , DOI: 10.1016/j.molimm.2020.12.021
Xing-Bo Mo , Yong-Hong Zhang , Shu-Feng Lei

Genome-wide association studies have identified many genetic loci for rheumatoid arthritis (RA). However, causal factors underlying these loci were largely unknown. The aim of this study was to identify potential causal methylation-mRNA regulation chains for RA. We identified differentially expressed mRNAs and methylations and conducted summary statistic data-based Mendelian randomization (SMR) analysis to detect potential causal mRNAs and methylations for RA. Then causal inference test (CIT) was performed to determine if the methylation-mRNA pairs formed causal chains. We identified 11,170 mRNAs and 24,065 methylations that were nominally associated with RA. Among them, 197 mRNAs and 104 methylations passed the SMR test. According to physical positions, we defined 16 cis methylation-mRNA pairs and inferred 5 chains containing 4 methylations and 4 genes (BACH2, MBP, MX1 and SYNGR1) to be methylation→mRNA→RA causal chains. The effect of SYNGR1 expression in peripheral blood mononuclear cells on RA risk was found to be consistent in both the in-house and public data. The identified methylations located in CpG Islands that overlap promoters in the 5′ region of the genes. The promoter regions showed long-range interactions with other enhancers and promoters, suggesting a regulatory potential of these methylations. Therefore, the present study provided a new integrative analysis strategy and highlighted potential causal methylation-mRNA chains for RA. Taking the evidences together, SYNGR1 promoter methylations most probably affect mRNA expressions and then affect RA risk.



中文翻译:

综合分析确定类风湿关节炎的潜在因果甲基化-mRNA调节链

全基因组关联研究已经确定了类风湿关节炎(RA)的许多遗传基因座。但是,这些基因位点的潜在因果在很大程度上尚不清楚。这项研究的目的是确定RA的潜在因果甲基化-mRNA调控链。我们鉴定了差异表达的mRNA和甲基化,并进行了基于统计数据的摘要孟德尔随机(SMR)分析,以检测RA的潜在因果mRNA和甲基化。然后进行因果推断测试(CIT)以确定甲基化-mRNA对是否形成因果链。我们确定了名义上与RA相关的11,170个mRNA和24,065个甲基化。其中有197个mRNA和104个甲基化通过了SMR测试。根据体位,我们定义了16个顺式甲基化-mRNA对,并推断出包含4个甲基化和4个基因(BACH2MBPMX1SYNGR1)的5条链为甲基化→mRNA→RA因果链。SYNGR1的作用在内部和公共数据中发现外周血单个核细胞中存在RA风险的表达是一致的。位于CpG岛中且与基因5'区域中的启动子重叠的甲基化。启动子区域显示与其他增强子和启动子的远程相互作用,表明这些甲基化的调节潜力。因此,本研究提供了一种新的综合分析策略,并强调了RA的潜在因果甲基化-mRNA链。综合考虑,SYNGR1启动子甲基化最有可能影响mRNA表达,然后影响RA风险。

更新日期:2020-12-30
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