AUTHOR=Lou Chen , Meng Zhizhen , Shi Yi-Yi , Zheng Rui , Qian Song-Zan , Pan Jingye 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1217922

DOI=10.3389/fcvm.2023.1217922

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Materials and methods</title><p>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.</p></sec><sec><title>Results</title><p>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; <italic>P</italic> = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598–0.963; <italic>P</italic> = 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; <italic>P</italic> = 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 (<inline-formula><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="IM1"><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mrow><mml:mi mathvariant="normal">OR</mml:mi></mml:mrow></mml:mrow></mml:mfrac></mml:mrow></mml:math></inline-formula>, 0.719 per SD reduction in LDL-C; 95% CI, 0.540–0.958; <italic>P</italic> = 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.</p></sec><sec><title>Conclusions</title><p>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.</p></sec>