The relationship between high density lipoprotein cholesterol and sepsis: A clinical and genetic approach

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.