Xu Yudi, Zhang Xiaowei, Zhang Yuyuan, Ma Hongxuan, Zhou Zhaokai, Qin Hongzhuo, Liu Huimin, Han Xinwei
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Neurobiol Dis. 2025 Jun 15;210:106929. doi: 10.1016/j.nbd.2025.106929. Epub 2025 Apr 23.
Oxidative stress (OS) is a key pathophysiological mechanism in multiple sclerosis (MS). However, the underlying mechanisms by which OS triggered MS remain unknown. To identify potential causal targets of 1216 OS-related genes for MS, a summary-data-based Mendelian randomization (SMR) method was applied. Given that genes can exert their biological functions through different omics levels, the multi-omics SMR integrating expression, methylation, and protein quantitative trait loci (eQTL, mQTL, and pQTL) of OS-related genes from blood and brain tissues was utilized. Bayesian colocalization test was conducted to examine potential regulatory mechanisms of QTL risk variation in MS. To verify the robustness of our results, we validated these findings in FinnGen cohort. Furthermore, the QTL evidence levels, colocalization findings, and replication cohort results were integrated and potential target genes were categorized into three levels. Consequently, three genes (BACH2, TRAF3, and MAPK3) were identified as potential contributors to MS in blood, and four genes (HMGCL, TSFM, TRAF3 and HLA-B) were identified as potential contributors to MS in brain tissue. Additionally, HMGCL and TSFM from brain tissue were supported by first-level evidence related to MS and were validated via in vitro experiments. This research not only contributed to fundamental research of OS in MS but also supported the identification of potential targets for clinical interventions in MS.
氧化应激（OS）是多发性硬化症（MS）的关键病理生理机制。然而，OS引发MS的潜在机制仍不清楚。为了确定1216个与OS相关基因作为MS的潜在因果靶点，应用了基于汇总数据的孟德尔随机化（SMR）方法。鉴于基因可通过不同组学水平发挥其生物学功能，利用了整合血液和脑组织中与OS相关基因的表达、甲基化和蛋白质数量性状位点（eQTL、mQTL和pQTL）的多组学SMR。进行了贝叶斯共定位检验，以研究MS中QTL风险变异的潜在调控机制。为了验证我们结果的稳健性，我们在芬兰基因队列中验证了这些发现。此外，整合了QTL证据水平、共定位结果和复制队列结果，并将潜在的靶基因分为三个水平。因此，三个基因（BACH2、TRAF3和MAPK3）被确定为血液中MS的潜在促成因素，四个基因（HMGCL、TSFM、TRAF3和HLA-B）被确定为脑组织中MS的潜在促成因素。此外，脑组织中的HMGCL和TSFM得到了与MS相关的一级证据的支持，并通过体外实验得到验证。这项研究不仅有助于MS中OS的基础研究，也为MS临床干预潜在靶点的识别提供了支持。
