Potential drug targets for systemic lupus erythematosus identified through Mendelian randomization analysis

So far, there is no clear pathogenesis and no cure for systemic lupus erythematosus (SLE). The therapeutic benefits of existing drug therapies are far from ideal. The proteome is a major source of therapeutic targets. Therefore, new drug targets for SLE need to be discovered. Based on the STROBE-Mendelian randomization (MR) checklist, we performed MR to explore potential drug targets for SLE, using genome-wide association study summary statistics of plasma and cerebrospinal fluid (CSF) and further replicated in the external validation. Bidirectional MR, reverse causality testing by Steiger filtering, Bayesian co-localization were used. In addition, protein-protein interaction networks (PPI) were performed to reveal potential associations between proteins and current SLE drugs. At false discovery rate (FDR) significance (PFDR < .05), MR analysis revealed 8 proteins. Five proteins decreased the SLE risks, whereas the other 3 proteins increased the SLE risks. None of the 8 proteins had reverse causality except sICAM-1. Bayesian co-localization suggested that 5 proteins shared the same variant with SLE. PPI network suggested that intercellular adhesion molecular 1 (ICAM-1), Fc-gamma-RIIb (FCG2B) and N-terminal pro-B-type natriuretic peptide (N-terminal pro-BNP) interacted with targets of current SLE medications. Our integrative analysis revealed that SLE risk is causally associated with ICAM-1, FCG2B, and N-terminal pro-BNP. These 3 proteins have the potential to become drug targets of SLE, especially for ICAM-1 and FCG2B. More further studies are also warranted to support this finding.