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

Chen Lou; Zhizhen Meng; Yi-Yi Shi; Rui Zheng; Song-Zan Qian; Jingye Pan

doi:10.3389/fcvm.2023.1217922

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

Front Cardiovasc Med. 2023 Aug 7:10:1217922. doi: 10.3389/fcvm.2023.1217922. eCollection 2023.

Authors

Chen Lou¹, Zhizhen Meng², Yi-Yi Shi³, Rui Zheng⁴, Song-Zan Qian⁵, Jingye Pan⁵

Affiliations

¹ School of The First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China.
² Department of Emergency, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
³ Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁵ Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

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 ( $\frac{1}{OR}$ , 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.

Keywords: Mendelian randomization (MR) analysis; genetic association; lipid; lipid-lowering drugs; sepsis.

Grants and funding

This work was supported by a grant from Research Incubation Project of the First Affiliated Hospital of Wenzhou Medical University (Grant NO. FHY2019048, WZ); Foundation of Wenzhou City Science & Technology Bureau (Y20210713); Wenzhou High-level Innovation Team for Critical Care and Intelligent Treatment (Grant No. 88923001).