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

Frontiers in Cardiovascular Medicine

Cardiovascular Medicine

Yi-Yi Shi¹  Rui Zheng²  Zhizhen Meng³  Song-Zan Qian⁴  Jingye Pan⁴  Chen Lou⁵ 

[1] Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China;Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China;Department of Emergency, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China;Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China;School of The First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China;

关键词: lipid-lowering drugs;    genetic association;    sepsis;    Mendelian randomization (MR) analysis;    lipid;   

DOI  :  10.3389/fcvm.2023.1217922

 received in 2023-05-10, accepted in 2023-07-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundThe 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 methodsData 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.ResultsIn 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© 2023 Lou, Meng, Shi, Zheng, Qian and Pan.