Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
School of Pharmaceutical Sciences, Capital Medical University, Beijing, China.
Front Immunol. 2024 Jul 15;15:1428962. doi: 10.3389/fimmu.2024.1428962. eCollection 2024.
Multiple sclerosis (MS) represents a multifaceted autoimmune ailment, prompting the development and widespread utilization of numerous therapeutic interventions. However, extant medications for MS have proven inadequate in mitigating relapses and halting disease progression. Innovative drug targets for preventing multiple sclerosis are still required. The objective of this study is to discover novel therapeutic targets for MS by integrating single-cell transcriptomics and Mendelian randomization analysis.
The study integrated MS genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data for analysis and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and MS. Sequential analyses involving colocalization and Phenome-wide association studies (PheWAS) were conducted to validate the causal role of candidate genes.
Following stringent quality control preprocessing of scRNA-seq data, 1,123 expression changes across seven peripheral cell types were identified. Among the seven most prevalent cell types, 97 genes exhibiting at least one eQTL were discerned. Examination of MR associations between 28 proteins with available index pQTL signals and the risk of MS outcomes was conducted. Co-localization analyses and PheWAS indicated that FCRL3 may exert influence on MS.
The integration of scRNA-seq and MR analysis facilitated the identification of potential therapeutic targets for MS. Notably, FCRL3, implicated in immune function, emerged as a significant drug target in the deCODE databases. This research underscores the importance of FCRL3 in MS therapy and advocates for further investigation and clinical trials targeting FCRL3.
多发性硬化症（MS）是一种多方面的自身免疫性疾病，促使人们开发并广泛应用了许多治疗干预措施。然而，现有的 MS 药物在减轻复发和阻止疾病进展方面效果有限。仍然需要寻找用于 MS 的创新药物靶点。本研究旨在通过整合单细胞转录组学和孟德尔随机化分析来发现 MS 的新治疗靶点。
该研究整合了 MS 全基因组关联研究（GWAS）数据、单细胞转录组学（scRNA-seq）、表达数量性状基因座（eQTL）和蛋白质数量性状基因座（pQTL）数据进行分析，并利用两样本孟德尔随机化研究来理解蛋白质与 MS 之间的因果关系。进行了连锁分析和表型全基因组关联研究（PheWAS）的顺序分析，以验证候选基因的因果作用。
对 scRNA-seq 数据进行严格的质量控制预处理后，确定了 7 种外周细胞类型中 1123 个表达变化。在这 7 种最常见的细胞类型中，发现了 97 个至少有一个 eQTL 的基因。对 28 种具有可用索引 pQTL 信号的蛋白质与 MS 结局风险之间的 MR 关联进行了检查。共定位分析和 PheWAS 表明，FCRL3 可能对 MS 有影响。
单细胞转录组学和 MR 分析的整合有助于确定 MS 的潜在治疗靶点。值得注意的是，deCODE 数据库中的 FCRL3 参与免疫功能，是一个重要的药物靶点。这项研究强调了 FCRL3 在 MS 治疗中的重要性，并提倡进一步研究和临床试验针对 FCRL3。
