Bidirectional Mendelian Randomization Reveals IL-17C as a Protective Factor and Sepsis-Induced Inflammatory Protein Dynamics

Background Numerous observational studies have established a link between circulating inflammatory proteins and sepsis. However, the connection between cause and effect remains unclear.  We investigated the cause-and-effect link between circulating inflammatory proteins and sepsis by using two-sample bidirectional Mendelian randomization (MR).Methods Genetic variation for 91 circulating inflammatory proteins was derived from genome-wide protein quantitative trait loci (pQTL) involving 14,824 participants of European ancestry. Genetic associations related to sepsis were extracted from the UK biobank European pedigree GWAS data (11643 cases and 474841 controls). The investigation into the causes of exposures and outcomes primarily employed the inverse variance weighting (IVW) method, complemented by various sensitivity assessments like MR-Egger, weighted median, Cochran's Q test, leave-one-out test, and MR-PRESSO test to solidify the ultimate findings.Results Genetically predicted increased levels of IL-17C were correlate with a reduced likelihood of sepsis. (OR = 0.87, 95% CI 0.77-0.98, p = 0.025). However, sepsis is associated with reduced CCL28 levels and increased concentrations of HGF, IL-12B, MCP-4, MIP-1α, and STAMBP. (OR = 0.89, 95% CI 0.79-1.00, p = 0.043; OR = 1.19, 95% CI 1.06-1.34, p = 0.004; OR = 1.18, 95% CI 1.03-1.34, p = 0.016; OR = 1.18, 95% CI 1.01-1.38, p = 0.034; OR = 1.15, 95% CI 1.02-1.29, p = 0.022; OR = 1.13, 95% CI 1.01-1.28, p = 0.038).Conclusion This study highlighted the correlation between several inflammation-related circulating proteins and sepsis. IL-17C is probably a factor correlated with sepsis etiology, while the remaining circulating inflammatory proteins are probably more engaged in the downstream of sepsis progression and may serve as a diagnostic marker of sepsis.