Chen Xiaokun, Jiang Guohua, Zhao Tianjing, Sun Nian, Liu Shanshan, Guo Hao, Zeng Canjun, Liu Yijun
Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai, China.
Department of Foot and Ankle Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Cell Biosci. 2024 Dec 5;14(1):147. doi: 10.1186/s13578-024-01323-4.
Diabetic polyneuropathy (DPN) is a common diabetes complication with limited treatment options. We aimed to identify circulating plasma proteins as potential therapeutic targets for DPN using Mendelian Randomization (MR).
The protein quantitative trait loci (pQTLs) utilized in this study were derived from seven previously published genome-wide association studies (GWASs) on plasma proteomics. The DPN data were obtained from the IEU OpenGWAS project. This study employed two-sample MR using MR-Egger and inverse-variance weighted methods to evaluate the causal relationship between plasma proteins and DPN risk, with Cochran's Q test, and I statistics, among other methods, used to validate the robustness of the results.
Using cis-pQTLs as genetic instruments, we identified 62 proteins associated with DPN, with 33 increasing the risk and 29 decreasing the risk of DPN. Using cis-pQTLs + trans-pQTLs, we identified 116 proteins associated with DPN, with 44 increasing the risk and 72 decreasing the risk of DPN. Steiger directionality tests indicated that the causal relationships between circulating plasma proteins and DPN were consistent with expected directions.
This study identified 96 circulating plasma proteins with genetically determined levels that affect the risk of DPN, providing new potential targets for DPN drug development, particularly ITM2B, CREG1, CD14, and PLXNA4.
糖尿病性多发性神经病（DPN）是一种常见的糖尿病并发症，治疗选择有限。我们旨在利用孟德尔随机化（MR）确定循环血浆蛋白作为DPN的潜在治疗靶点。
本研究中使用的蛋白质定量性状位点（pQTLs）来自之前发表的七项关于血浆蛋白质组学的全基因组关联研究（GWASs）。DPN数据来自IEU OpenGWAS项目。本研究采用两样本MR，使用MR-Egger和逆方差加权方法评估血浆蛋白与DPN风险之间的因果关系，并用Cochran's Q检验和I统计量等方法验证结果的稳健性。
使用顺式pQTLs作为遗传工具，我们鉴定出62种与DPN相关的蛋白质，其中33种增加DPN风险，29种降低DPN风险。使用顺式pQTLs + 反式pQTLs，我们鉴定出116种与DPN相关的蛋白质，其中44种增加DPN风险，72种降低DPN风险。Steiger方向性检验表明，循环血浆蛋白与DPN之间的因果关系与预期方向一致。
本研究鉴定出96种循环血浆蛋白，其基因决定水平影响DPN风险，为DPN药物开发提供了新的潜在靶点，特别是ITM2B、CREG1、CD14和PLXNA4。
