Table_2_Exploring causal correlations between plasma proteins and peripheral neuropathy: a Mendelian randomization.xlsx

BackgroundPeripheral neuropathy (PN) is a common neurological disorder, and circulating plasma proteins with causal genetic evidence are a major source of therapeutic targets. This study identifies several potential plasma proteins that are causally related to PN risk, providing new insights into protein-mediated pathogenesis of PN and potential targets for novel therapies.
MethodsTo identify potential therapeutic targets for PN, we employed two-sample Mendelian randomization (MR) to identify plasma proteins associated with six common PN. First, we screened for proteins related to PN using genome-wide association studies (GWAS), obtaining genetic data on plasma proteomes from 35,559 Icelanders. Summary data for six common PN, including Carpal Tunnel Syndrome (CTS), Trigeminal Neuralgia (TN), Alcoholic Neuropathy (AIP), Drug-induced Neuropathy (DIP), Diabetic Neuropathy (DP), and Guillain-Barré syndrome (GBS), were obtained from the FinnGen database. Two-sample MR and colocalization analyses were then conducted to further identify protein-PN pairs with presumed causal relationships. Enrichment analysis of positive proteins revealed potential biological processes and pathways. Based on drug-gene interaction analysis, we ultimately identified causal proteins associated with PN that could serve as potential drug targets for treating PN.
ResultsThrough MR analysis, we identified eight proteins (UBC12, SEM4C, IL23R, Prothrombin, CBS, Microglobulin, MATN4, COLEC12) with causal relationships to PN. We found that UBC12 is a protective factor for DP and CTS, while the remaining proteins are risk factors. Further colocalization analysis showed a posterior probability of hypothesis 4 (PPH4) less than 0.75, indicating no positive colocalization results were found. From the pathway enrichment analysis, we discovered that the proteins were mainly concentrated in pathways related to defense response to bacterium, receptor signaling pathway via STAT, cell killing, negative regulation of cytokine production, and leukocyte mediated immunity. Finally, in Drug-Gene Interaction database (DGIdb), we identified three protein-coding genes (IL23R, F2, CBS) as potential drug targets for PN.
ConclusionMendelian randomization studies confirm the causal relationship between genetically predicted PN-related risk and genetically predicted plasma protein abundance. Plasma proteins, as biomarkers associated with PN, can provide potential drug targets for etiological intervention research in PN.

背景：周围神经病（Peripheral Neuropathy, PN）是一种常见神经系统疾病，具备因果遗传证据的循环血浆蛋白是治疗靶点的重要来源。本研究鉴定出数种与周围神经病发病风险存在因果关联的潜在血浆蛋白，为阐明周围神经病的蛋白介导发病机制提供了新视角，并为新型治疗方案提供了潜在靶点。
方法：为鉴定周围神经病的潜在治疗靶点，本研究采用双样本孟德尔随机化（Two-sample Mendelian Randomization, MR）方法，筛选与六种常见周围神经病相关的血浆蛋白。首先，我们基于全基因组关联研究（Genome-Wide Association Studies, GWAS）筛选与周围神经病相关的蛋白，从35559名冰岛人群中获取血浆蛋白质组的遗传数据。六种常见周围神经病的汇总数据，包括腕管综合征（Carpal Tunnel Syndrome, CTS）、三叉神经痛（Trigeminal Neuralgia, TN）、酒精性神经病（Alcoholic Neuropathy, AIP）、药物性神经病（Drug-induced Neuropathy, DIP）、糖尿病性神经病（Diabetic Neuropathy, DP）以及吉兰-巴雷综合征（Guillain-Barré Syndrome, GBS），均来自FinnGen数据库。随后开展双样本孟德尔随机化及共定位分析，进一步筛选具有潜在因果关联的蛋白-周围神经病配对。对阳性关联蛋白进行富集分析，以揭示潜在的生物学过程及通路。基于药物-基因相互作用分析，我们最终鉴定出与周围神经病存在因果关联的蛋白，可作为治疗周围神经病的潜在药物靶点。
结果：通过孟德尔随机化分析，我们鉴定出8种与周围神经病存在因果关联的蛋白（UBC12、SEM4C、IL23R、凝血酶原、CBS、微球蛋白、MATN4、COLEC12）。其中UBC12是糖尿病性神经病与腕管综合征的保护因子，其余蛋白均为风险因子。进一步共定位分析显示，假设4的后验概率（PPH4）小于0.75，提示未发现阳性共定位结果。通路富集分析发现，上述蛋白主要富集于细菌防御反应、经STAT的受体信号通路、细胞杀伤、细胞因子产生负调控以及白细胞介导的免疫等相关通路。最后，在药物-基因相互作用数据库（Drug-Gene Interaction database, DGIdb）中，我们鉴定出3个蛋白编码基因（IL23R、F2、CBS）可作为周围神经病的潜在药物靶点。
结论：孟德尔随机化研究证实了遗传预测的周围神经病发病风险与遗传预测的血浆蛋白丰度之间存在因果关联。血浆蛋白作为与周围神经病相关的生物标志物，可为周围神经病的病因干预研究提供潜在药物靶点。