Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, 215123, PR China.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, 215123, PR China.
Mol Immunol. 2021 Mar;131:89-96. doi: 10.1016/j.molimm.2020.12.021. Epub 2020 Dec 30.
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.
全基因组关联研究已经确定了许多类风湿关节炎（RA）的遗传位点。然而，这些位点背后的因果因素在很大程度上尚不清楚。本研究旨在确定 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，并进行了基于汇总统计数据的孟德尔随机化（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 11170 个 mRNA 和 24065 个与 RA 具有名义关联的甲基化。其中，197 个 mRNA 和 104 个甲基化通过了 SMR 测试。根据物理位置，我们定义了 16 个 cis 甲基化-mRNA 对，并推断出包含 4 个甲基化和 4 个基因（BACH2、MBP、MX1 和 SYNGR1）的 5 个链为甲基化→mRNA→RA 因果链。发现外周血单核细胞中 SYNGR1 表达对 RA 风险的影响在内部和公共数据中均一致。鉴定的甲基化位于基因 5'区域启动子重叠的 CpG 岛上。启动子区域与其他增强子和启动子具有长程相互作用，表明这些甲基化具有潜在的调控能力。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。综合这些证据，SYNGR1 启动子甲基化很可能影响 mRNA 表达，进而影响 RA 风险。
