The class
Genetic evidence suggests the HDL cholesterol-sepsis association is not causally mediated through CETP (Clin Transl Sci 2023)
Original title: The relationship between high density lipoprotein cholesterol and sepsis: A clinical and genetic approach
Since higher HDL cholesterol is clinically associated with apparent protection from sepsis, raising the possibility that CETP inhibitors could help by raising HDL-C, researchers tested this causal hypothesis genetically in 73,406 White adults hospitalised with infection at Vanderbilt University Medical Center, of whom 11,612 had measured HDL-C and 12,377 had genotype data used to build polygenic risk scores for HDL-C and for the effect of CETP on HDL-C. Lower measured HDL-C was significantly associated with increased risk of sepsis, septic shock, respiratory failure and in-hospital death in unadjusted analyses, though these associations were markedly attenuated after adjustment for confounders. While the HDL-C polygenic score, the CETP polygenic score, and the CETP variant rs1800777 all significantly predicted HDL-C levels, none were associated with sepsis outcomes, a pattern also observed in 13,254 Black patients, indicating that although low HDL-C tracks with worse sepsis outcomes, this relationship is unlikely to be causally mediated through CETP.
Original abstract
Sepsis accounts for one in three hospital deaths. Higher concentrations of high-density lipoprotein cholesterol (HDL-C) are associated with apparent protection from sepsis, suggesting a potential therapeutic role for HDL-C or drugs, such as cholesteryl ester transport protein (CETP) inhibitors that increase HDL-C. However, these beneficial clinical associations might be due to confounding; genetic approaches can address this possibility. We identified 73,406 White adults admitted to Vanderbilt University Medical Center with infection; 11,612 had HDL-C levels, and 12,377 had genotype information from which we constructed polygenic risk scores (PRS) for HDL-C and the effect of CETP on HDL-C. We tested the associations between predictors (measured HDL-C, HDL-C PRS, CETP PRS, and rs1800777) and outcomes: sepsis, septic shock, respiratory failure, and in-hospital death. In unadjusted analyses, lower measured HDL-C concentrations were significantly associated with increased risk of sepsis (p = 2.4 × 10-23 ), septic shock (p = 4.1 × 10-12 ), respiratory failure (p = 2.8 × 10-8 ), and in-hospital death (p = 1.0 × 10-8 ). After adjustment (age, sex, electronic health record length, comorbidity score, LDL-C, triglycerides, and body mass index), these associations were markedly attenuated: sepsis (p = 2.6 × 10-3 ), septic shock (p = 8.1 × 10-3 ), respiratory failure (p = 0.11), and in-hospital death (p = 4.5 × 10-3 ). HDL-C PRS, CETP PRS, and rs1800777 significantly predicted HDL-C (p < 2 × 10-16 ), but none were associated with sepsis outcomes. Concordant findings were observed in 13,254 Black patients hospitalized with infections. Lower measured HDL-C levels were significantly associated with increased risk of sepsis and related outcomes in patients with infection, but a causal relationship is unlikely because no association was found between the HDL-C PRS or the CETP PRS and the risk of adverse sepsis outcomes.
the classgeneticsinfectioninflammationsafety
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.