Mendelian randomisation finds genetically proxied CETP inhibitors protect against sepsis, an effect explained largely by ApoA-I (Front Cardiovasc Med 2023)

Original title: Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis

Front Cardiovasc Med · 1 January 2023 · 6

Lou C, Meng Z, Shi YY, Zheng R, Qian SZ, Pan J

A Mendelian randomisation and mediation study tested causal links between genetically determined lipids, lipid-lowering drugs and sepsis risk, using MR-Base and Global Lipids Genetics Consortium data, splitting outcomes into total sepsis and 28-day sepsis mortality (sepsis28). ApoA-I suggestively protected against both total sepsis (odds ratio 0.863 per SD increase, 95% CI, 0.780 to 0.955) and sepsis28 (odds ratio 0.759), and higher HDL-C suggestively reduced total sepsis risk (odds ratio 0.891). In drug-target Mendelian randomisation, HMGCR inhibitors protected against total sepsis, and both LDL-C- and HDL-C-proxied CETP inhibitors showed a protective effect on total sepsis, with the LDL-C-proxied CETP inhibitor effect also suggestively protective against sepsis28. Mediation analysis found the indirect effect of ApoA-I explained over 50% of the protective effect of CETP inhibitors on sepsis. A genetic epidemiology signal, complementing mouse mechanistic work on CETP inhibition and sepsis, not a clinical trial result.

Original abstract

Background: The impact of lipid-lowering medications on sepsis is still not well defined. A Mendelian randomization (MR) study was carried out to probe the causal connections between genetically determined lipids, lipid-reducing drugs, and the risk of sepsis.

Materials And Methods: Data on total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and triglycerides (TG) were retrieved from the MR-Base platform and the Global Lipids Genetics Consortium in 2021 (GLGC2021). Our study categorized sepsis into two groups: total sepsis and 28-day mortality of sepsis patients (sepsis28). The inverse-variance weighted (IVW) method was the primary method used in MR analysis. Cochran's Q test and the MR-Egger intercept method were used to assess the heterogeneity and pleiotropy.

Results: In the MR analysis, we found that ApoA-I played a suggestively positive role in protecting against both total sepsis (OR, 0.863 per SD increase in ApoA-I; 95% CI, 0.780-0.955; P = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598-0.963; P = 0.023). HDL-C levels were also found to suggestively reduce the incidence of total sepsis (OR, 0.891 per SD increase in HDL-C; 95% CI, 0.802-0.990; P = 0.031). Reverse-MR showed that sepsis28 led to a decrease in HDL-C level and an increase in TG level. In drug-target MR, we found that HMGCR inhibitors positively protected against total sepsis (1OR, 0.719 per SD reduction in LDL-C; 95% CI, 0.540-0.958; P = 0.024). LDL-C and HDL-C proxied CETP inhibitors were found to have a protective effect on total sepsis, with only LDL-C proxied CETP inhibitors showing a suggestively protective effect on sepsis28. In Mediated-MR, BMI exhibited a negative indirect effect in HMGCR inhibitors curing sepsis. The indirect impact of ApoA-I explained over 50% of the curative effects of CETP inhibitors in sepsis.

Conclusions: Our MR study suggested that ApoA-I and HDL-C protected against sepsis, while HMGCR and CETP inhibitors showed therapeutic potential beyond lipid-lowering effects. ApoA-I explained the effects of CETP inhibitors. Our study illuminates how lipids affect sepsis patients and the effectiveness of new drugs, opening new avenues for sepsis treatment.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.