Genetic Latent Factor-Aided Identification of Protein Targets to Prioritize Drug Repurposing Candidates for Primary Membranous Nephropathy

Objectives : Previous target identification studies for primary membranous nephropathy (pMN) were vulnerable to false positives due to the rare nature of pMN, limiting their clinical plausibility. We aimed to identify robust protein targets for pMN and discover drug repurposing candidates modulating these targets.
Methods : We proposed a three-stage framework that first discovers autoimmune latent factors with sufficient power and shared genetic architecture to pMN, followed by identification of causal protein quantitative traits and drug repurposing candidates. First, genetic latent factors were modeled using genomic structural equation modeling on genetic data of autoimmune diseases from the FinnGen Project. Second, a large-scale cis-Mendelian randomization analysis of 1,888 plasma proteins from the UK Biobank on the latent factor was conducted to screen candidate targets, followed by a confirmatory analysis on pMN. Validation analysis was performed using deCODE genetics data to assess replicability. Third, proteins directly interacting with causal proteins were identified via a protein-protein interaction network, and corresponding drug repurposing candidates were identified via reviewing clinical development status.
Results : A systemic autoimmune disease latent factor (ξ_S)—comprising Graves’ disease, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus—showed significant genetic covariance with pMN (P = 0.045). Among 37 traits screened from ξ_S, FCRL1 (odds ratio [OR]: 1.378, P = 5.7×10^-7), FCRL2 (OR: 1.262, P = 2.2×10^-4), and FCRL3 (OR: 1.161, P = 1.1×10^-4) were identified as causal proteins on pMN. Causal effects of FCRL1 and FCRL3 were replicated with marginal statistical significance (P < 0.10). Network analysis revealed a direct interaction between FCRL3 and CD40. Consequently, CD40(L) antagonists—including iscalimab, abiprubart, dapirolizumab pegol, and dazodalibep—were identified as drug repurposing candidates.
Conclusions : Our findings establish the causal role of the FCRL protein family in pMN with robust replicability. By identifying CD40(L) antagonists as potential therapeutic candidates, this study provides genetic evidence for a clinically plausible drug repurposing strategy for pMN.