Department of Neurology, Xuanwu Hospital, National Center for Neurological Disorders, Capital Medical University, Beijing, 100053, China.
Beijing Municipal Geriatric Medical Research Center, Beijing, China.
J Transl Med. 2024 Mar 24;22(1):302. doi: 10.1186/s12967-024-04994-2.
Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG.
By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk.
We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in T2 cells and MG risk.
This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.
重症肌无力（MG）是一种慢性自身免疫性疾病，其特征是肌肉无力波动。尽管有已建立的治疗方法，但 MG 症状的管理仍不理想，部分原因是缺乏疗效或无法耐受的副作用。因此，需要新的有效药物来治疗 MG。
通过采用结合孟德尔随机化（MR）和共定位分析的分析框架，我们估计血液可药物治疗的表达数量性状基因座（eQTLs）和蛋白质数量性状基因座（pQTLs）对 MG 易感性的因果影响。随后，我们通过利用遗传共定位分析来评估免疫细胞特异性 eQTLs 与 MG 风险之间的相互作用，研究潜在的遗传效应是否具有细胞类型特异性。
我们使用顺式-eQTL 遗传工具鉴定了四个基因（CDC42BPB、CD226、PRSS36 和 TNFSF12）和三个蛋白质（CTSH、PRSS8 和 CPN2）的显著 MR 结果。其中六个基因座与 MG 易感性存在共定位证据（后验概率>0.80）。我们接下来进行了遗传共定位，以研究这些基因座的细胞类型特异性效应。值得注意的是，我们鉴定出了强有力的共定位证据，后验概率为 0.854，表明 T2 细胞中 CTSH 的表达与 MG 风险相关。
本研究提供了与 MG 易感性相关的遗传和分子因素的重要见解，确定 CTSH 为深入研究和临床考虑的潜在候选基因。此外，它还揭示了与疾病相关的免疫细胞调节机制。然而，需要进一步的研究来验证这些靶点，并评估它们在药物开发中的可行性。
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