Identification of circulating inflammatory proteins as potential drug targets for sepsis through Mendelian randomization and colocalization analyses

Sepsis is a complex disease with limited therapeutics. We conducted a 2-sample Mendelian randomization (MR) analysis to identify circulating inflammatory proteins as potential drug targets for sepsis. Protein quantitative trait loci (pQTLs) at cis-region for 448 circulating inflammatory proteins were obtained from the UK biobank pharma proteomics project (UKB-PPP) (N = 54219), and summary-level genetic associations with sepsis were extracted from the FinnGen cohort (12,301 cases and 332,343 controls) for the primary MR analysis. The findings were further replicated using alternative cis-pQTL (Fenland, N = 10708) and sepsis genome-wide association study data (UK Biobank, 2811 cases and 406,150 controls). Multiple sensitivity analyses including summary-data-based MR (SMR), the HEIDI test, colocalization, and phenome-wide scanning were performed to verify the causality of the identified proteins. Moreover, protein–protein interaction analysis was performed to examine the interactions between identified proteins and current drug targets in clinical trials. With the adjusted P -value <.05, 1-SD increase in genetically determined APOE (apolipoprotein E) was associated with increased risk of sepsis (OR = 1.07, 95%CI = 1.04–1.11, P  = 5.36 × 10 ⁻⁵ ). The findings were consistent in the validation analyses. Multi-SNPs SMR analysis ( P  = 1.42 × 10 ⁻³ ), HEIDI test ( P  = .53), and colocalization analysis (PP4 = 0.95) further supported the causality of APOE. Protein–protein interaction analysis suggested that APOE was interacted with multiple drug targets tested in the clinical trials for sepsis. This integrative analysis combing the pQTL and genome-wide association study data identified APOE as a promising drug target for sepsis. Further experimental studies were warranted to explore the details of the underlying biological mechanisms and feasibility of drug development.