Causal relationships between antibody-induced immune responses and sepsis: Evidence from genetic studies

The causal relationships between antibody-induced immune responses and the occurrence and mortality of sepsis remain controversial. The 2-sample Mendelian randomization (MR) approach was utilized to reveal the causal associations, along with the potential mediation effects of inflammatory cytokines. The causal associations were analyzed by a 2-sample bidirectional MR analysis, primarily using the inverse variance weighted method. MR-Egger regression, weighted mode, weighted median, and simple mode were conducted as supplementary analyses. Additionally, we performed a 2-step MR to investigate the potential mediation effects of 91 inflammatory cytokines. Cochran Q test was conducted to assess statistical heterogeneity. Potential horizontal pleiotropy was identified with MR-Egger regression intercept test and MR-pleiotropy residual sum and outlier global test. Leave-one-out sensitivity analysis was employed to evaluate the influence of an individual single nucleotide polymorphism on the estimates. The outcomes revealed positive associations between genetically predicted Helicobacter pylori urea antibody levels (odds ratios [ORs] = 1.070, 95% confidence interval [CI]: 1.009-1.134, P = .024), anti-herpes simplex virus type 1 immunoglobulin G seropositivity [OR = 1.071, 95% CI: 1.012-1.134, P = .018], and the risk of sepsis; cytomegalovirus phosphoprotein 52 antibody levels showed significant negative correlation with 28-day mortality in sepsis [OR = 0.830, 95% CI: 0.690-0.999, P = .048]. Surprisingly, the mediation analysis suggested that the 91 inflammatory cytokines did not mediate these associations. H pylori urea antibody and anti-herpes simplex virus type 1 immunoglobulin G seropositivity are pathogenic factors for sepsis, while cytomegalovirus phosphoprotein 52 antibody levels may protect against 28-day mortality in sepsis. Inflammatory cytokines may not mediate these relationships. These findings could contribute to the precise management of sepsis.