Abstract

Background 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.

Methods We utilized summary statistics of MN from the Kiryluk Lab and obtained data on 1699 plasma proteins from recently published genome-wide association studies. We performed a two-sample Mendelian randomization analysis and employed Steiger filtering for reverse causal relationship detection, Bayesian colocalization, phenotype scanning, and protein-protein interaction network.

Results The Mendelian randomization analysis uncovered 60 distinct proteins associated with MN. Proteins associated with an increased risk of MN in plasma include VWF [(Von Willebrand Factor) (WR OR = 1.412, 95%CI : 1.157-1.725, P=0.0007)], TLL1 [ (Tolloid-Like Protein 1) (WR OR = 1.353, 95%CI : 1.033-1.773, P=0.028, PPH4 = 0.986) ], REG3G[ (Regenerating Family Member 3 Gamma) (WR OR = 1.353, 95%CI : 1.033-1.773, P=0.047, PPH4 = 0.542)], PROC [(Vitamin K-Dependent Protein C) (WR OR = 1.203, 95%CI : 1.023-1.407, P=0.021)] and NCAM1[(Neural Cell Adhesion Molecule 1) (IVW OR = 1.391, 95%CI : 1.019-1.899, P=0.037)], etc.. In contrast, proteins with protective effects against MN include CD27 [(Cd27 Antigen) ( WR OR = 0.785, 95%CI : 0.681-0.904, P=0.0008)] and HRG[(Histidine-Rich Glycoprotein)(WR OR = 0.839, 95%CI : 0.757-0.930, P=0.0008)], etc. After False Discovery Rate multiple correction, CD27 (P= 0.031), VWF (P= 0.031) and HRG (P= 0.031) still remain significant. None of these proteins exhibited a reverse causal relationship. Bayesian colocalization analysis provided evidence that TLL1 and REG3G share variants with MN. We found the interaction between CD27, NCAM1, PROC, and the target protein (CD20) of the targeted drug rituximab in MN.

Conclusions Our comprehensive analysis indicates a causal effect of CD27, VWF, HRG, TLL1, REG3G, NCAM1, and PROC at the genetically determined circulating levels on the risk of MN. NCAM1 has been confirmed as a pathogenic antigen in MN. These proteins have the potential to be a promising therapeutic target for the treatment of MN, warranting further clinical research.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Funding: Shenzhen Key Medical Discipline Construction Fund (SZXK009).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The data used for analysis in this study are publicly available, and we can download them from relevant articles for analysis.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors. The data used for analysis in this study are publicly available, and we can download them from relevant articles for analysis. We provide the PMID (PubMed ID) of some relevant articles: 29875488, 28240269, 30111768, 34648354, 30072576, 28369058 and 32231244.

List of abbreviationsMNMembranous nephropathyMRMendelian RandomizationGWASgenome-wide association studiesSNPssingle nucleotide polymorphismsIVsinstrumental variablesVWFVon Willebrand FactorWRWald RatioIVWinverse variance weightedOROdds Ratio95%CIConfidence IntervalPP-valueTLL1Tolloid-Like Protein 1PPHposterior probabilities of hypothesesREG3GRegenerating Family Member 3 GammaPROCVitamin K-Dependent Protein CNCAM1Neural Cell Adhesion Molecule 1CD27Cd27 AntigenHRGHistidine-Rich Glycoprotein.