Department of Nephrology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Front Immunol. 2024 Apr 19;15:1342912. doi: 10.3389/fimmu.2024.1342912. eCollection 2024.
The currently available medications for treating membranous nephropathy (MN) still have unsatisfactory efficacy in inhibiting disease recurrence, slowing down its progression, and even halting the development of end-stage renal disease. There is still a need to develop novel drugs targeting MN.
We utilized summary statistics of MN from the Kiryluk Lab and obtained plasma protein data from Zheng et al. We performed a Bidirectional Mendelian randomization analysis, HEIDI test, mediation analysis, Bayesian colocalization, phenotype scanning, drug bank analysis, and protein-protein interaction network.
The Mendelian randomization analysis uncovered 8 distinct proteins associated with MN after multiple false discovery rate corrections. Proteins related to an increased risk of MN in plasma include ABO [(Histo-Blood Group Abo System Transferase) (WR OR = 1.12, 95%CI:1.05-1.19, FDR=0.09, PPH4 = 0.79)], VWF [(Von Willebrand Factor) (WR OR = 1.41, 95%CI:1.16-1.72, FDR=0.02, PPH4 = 0.81)] and CD209 [(Cd209 Antigen) (WR OR = 1.19, 95%CI:1.07-1.31, FDR=0.09, PPH4 = 0.78)], and proteins that have a protective effect on MN: HRG [(Histidine-Rich Glycoprotein) (WR OR = 0.84, 95%CI:0.76-0.93, FDR=0.02, PPH4 = 0.80)], CD27 [(Cd27 Antigen) (WR OR = 0.78, 95%CI:0.68-0.90, FDR=0.02, PPH4 = 0.80)], LRPPRC [(Leucine-Rich Ppr Motif-Containing Protein, Mitochondrial) (WR OR = 0.79, 95%CI:0.69-0.91, FDR=0.09, PPH4 = 0.80)], TIMP4 [(Metalloproteinase Inhibitor 4) (WR OR = 0.67, 95%CI:0.53-0.84, FDR=0.09, PPH4 = 0.79)] and MAP2K4 [(Dual Specificity Mitogen-Activated Protein Kinase Kinase 4) (WR OR = 0.82, 95%CI:0.72-0.92, FDR=0.09, PPH4 = 0.80)]. ABO, HRG, and TIMP4 successfully passed the HEIDI test. None of these proteins exhibited a reverse causal relationship. Bayesian colocalization analysis provided evidence that all of them share variants with MN. We identified type 1 diabetes, trunk fat, and asthma as having intermediate effects in these pathways.
Our comprehensive analysis indicates a causal effect of ABO, CD27, VWF, HRG, CD209, LRPPRC, MAP2K4, and TIMP4 at the genetically determined circulating levels on the risk of MN. These proteins can potentially be a promising therapeutic target for the treatment of MN.
目前用于治疗膜性肾病（MN）的药物在抑制疾病复发、减缓其进展甚至阻止终末期肾病的发展方面仍不尽如人意。仍需要开发针对 MN 的新型药物。
我们利用 Kiryluk 实验室的 MN 汇总统计数据，并从 Zheng 等人处获得血浆蛋白数据。我们进行了双向孟德尔随机化分析、HEIDI 检验、中介分析、贝叶斯共定位、表型扫描、药物库分析和蛋白质-蛋白质相互作用网络分析。
孟德尔随机化分析揭示了 8 种与 MN 相关的不同蛋白质，经过多次错误发现率校正。与 MN 风险增加相关的血浆蛋白包括 ABO[（Histo-Blood Group Abo System Transferase）（WR OR = 1.12，95%CI：1.05-1.19，FDR=0.09，PPH4=0.79）]、VWF[（Von Willebrand Factor）（WR OR = 1.41，95%CI：1.16-1.72，FDR=0.02，PPH4=0.81）]和 CD209[（Cd209 Antigen）（WR OR = 1.19，95%CI：1.07-1.31，FDR=0.09，PPH4=0.78）]，以及对 MN 具有保护作用的蛋白质：HRG[（Histidine-Rich Glycoprotein）（WR OR = 0.84，95%CI：0.76-0.93，FDR=0.02，PPH4=0.80）]、CD27[（Cd27 Antigen）（WR OR = 0.78，95%CI：0.68-0.90，FDR=0.02，PPH4=0.80）]、LRPPRC[（Leucine-Rich Ppr Motif-Containing Protein，Mitochondrial）（WR OR = 0.79，95%CI：0.69-0.91，FDR=0.09，PPH4=0.80）]、TIMP4[（Metalloproteinase Inhibitor 4）（WR OR = 0.67，95%CI：0.53-0.84，FDR=0.09，PPH4=0.79）]和 MAP2K4[（Dual Specificity Mitogen-Activated Protein Kinase Kinase 4）（WR OR = 0.82，95%CI：0.72-0.92，FDR=0.09，PPH4=0.80）]。ABO、HRG 和 TIMP4 成功通过 HEIDI 检验。这些蛋白质均不存在反向因果关系。贝叶斯共定位分析提供了证据表明它们都与 MN 共享变体。我们确定 1 型糖尿病、躯干脂肪和哮喘在这些途径中具有中间效应。
我们的综合分析表明，ABO、CD27、VWF、HRG、CD209、LRPPRC、MAP2K4 和 TIMP4 在遗传决定的循环水平上对 MN 的风险具有因果影响。这些蛋白质可能是治疗 MN 的有前途的治疗靶点。
