Multiomics Mendelian randomization integrating pQTL, eQTL and mQTL data revealed BTN3A2 as a potential drug target for nephrolithiasis.

Nephrolithiasis has a high recurrence rate and imposes a heavy burden on patients and society. Therefore, there is an urgent need to explore new effective targets for nephrolithiasis prevention and treatment. Protein quantitative trait loci (pQTL) data of plasma proteins and plasma protein-protein ratios were used as plasma protein related targets (PPRTs), and genome-wide association studies (GWASs) of nephrolithiasis were used as outcomes. Bidirectional Mendelian randomization analyses were then conducted. The mediating factors between PPRTs and nephrolithiasis were identified. After colocalization analyses, the safety of targeted PPRTs for nephrolithiasis were evaluated. Subsequently, multi-omics data were used to further validate the effects of candidate PPRTs on nephrolithiasis. Finally, molecular docking operations were performed. Six PPRTs were confirmed to be causally associated with nephrolithiasis. The glomerular filtration rate (GFR) was identified as a mediating factor between five PPRTs and nephrolithiasis. There were strong evidences of colocalization of three PPRTs. After safety assessments and multi-omics analyses, BTN3A2 was considered as a potential therapeutic target. Molecular docking analyses indicated that digitoxigenin had the strongest binding ability with BTN3A2. These comprehensive analyses suggested causal relationships between PPRTs and nephrolithiasis, and BTN3A2 might be an advantageous drug target for nephrolithiasis.