| Summary: | Abstract Apolipoprotein AI (ApoAI), the main component of high-density lipoprotein (HDL), binds pathogen lipids to limit inflammation. We performed a retrospective analysis of 442,601 European patients in the UK Biobank (UKB) cohort focused on sepsis patients (n = 11,643). We tested for a causal contribution of ApoAI using Mendelian randomization with an ApoAI genetic score as an instrumental variable, with sensitivity analyses to control for genetic confounders and instrumental variable assumptions. Sensitivity analyses controlled for confounders, and validation was performed in transancestry sepsis cohorts VASST (Europeans, n = 632) and Chiba (East Asians, n = 536). Median baseline ApoAI levels were lower in individuals who later developed sepsis (1.45 g/L) than in those who did not (1.51 g/L; P < 0.0001). Mendelian randomization in UKB showed ApoAI as protective against sepsis incidence (OR = 0.87, 95%CI [0.86,0.89], P = 7.4 × 10− 44) and 28-day mortality (OR = 0.73, 95%CI [0.71,0.76], P = 8.2 × 10− 40). ApoAI’s protective effect on mortality was validated in VASST (OR = 0.84, 95%CI [0.72,0.99], P = 0.046) and Chiba (OR = 0.69, 95%CI [0.57,0.84], P = 0.0002). Confidence intervals overlapped between all cohorts indicating directional agreement of causal effect. Multivariable Mendelian randomization was performed to assess independence from other major lipid parameters. In multivariable analysis adjusting for HDL-C, LDL-C, and triglycerides, ApoAI retained a strong independent protective effect (OR = 0.71, 95%CI [0.65, 0.77], P = 2.4 × 10− 20). We further identified a putative mechanism. Specifically, ApoAI causally reduces circulating LPS levels (logOR=-0.23, 95%CI [– 0.22,-0.24], P = 9.1 × 10− 81). We conclude that plasma ApoAI levels provide significant causal protection in sepsis pathobiology possibly by reducing circulating LPS levels.
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