Exploring lipid-modifying therapies for sepsis through the modulation of circulating inflammatory cytokines: a Mendelian randomization study

doi:10.5847/wjem.j.1920-8642.2025.045

Abstract

Abstract:

BACKGROUND: Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain. Therefore, systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines, which may play critical roles in the pathogenesis of sepsis. This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.

METHODS: First, a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and sepsis. A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetically proxied lipid-modifying therapies on the risk of sepsis, sepsis-related critical care admission, and sepsis-related death. The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines. Finally, enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.

RESULTS: Genetically proxied cholesteryl ester transfer protein (CETP) inhibitors were significantly associated with sepsis-related critical care admission (OR=0.84, 95% CI [0.74, 0.95], P=0.008,) and sepsis-related death (OR=0.68, 95% CI [0.52, 0.88], P=0.004). The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines. Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.

CONCLUSION: This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death. These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines, influencing the inflammatory response pathway.

Key words: Lipid-modifying therapies, Sepsis, Mendelian randomization

Quan Li, Yun Qu, Jinfang Xue, Hai Kang, Chuanzhu Lyu. Exploring lipid-modifying therapies for sepsis through the modulation of circulating inflammatory cytokines: a Mendelian randomization study[J]. World Journal of Emergency Medicine, 2025, 16(3): 256-261.

Figures/Tables 3

Table 1.

Figure 1.

Figure 2.

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SNP	EA/NA	EAF	Effect (95% CI), mmol/L	P-value
CETP
rs12708967	T/C	0.80	0.194 (0.185, 0.203)	3.12×10^-326
rs1800775	A/C	0.48	0.202 (0.195, 0.209)	3.33×10^-644
rs1864163	G/A	0.73	0.225 (0.216, 0.233)	3.56×10^-573
rs289714	A/G	0.79	0.214 (0.205, 0.224)	8.72×10^-353
rs3764261	A/C	0.29	0.241 (0.234, 0.249)	1.39×10^-769
rs9929488	G/C	0.70	0.176 (0.167, 0.185)	1.15×10^-312
rs9989419	G/A	0.60	0.147 (0.140, 0.154)	1.79×10^-339
HMGCR
rs10515198	G/A	0.90	-0.060 (-0.072, -0.048)	5.99×10^-22
rs12173076	T/G	0.88	-0.065 (-0.076, -0.054)	2.33×10^-27
rs12916	T/C	0.57	-0.073 (-0.081, -0.066)	7.79×10^-78
rs3857388	T/C	0.87	-0.042 (-0.054, -0.031)	2.20×10^-11
rs7711235	A/G	0.73	-0.038 (-0.050, -0.025)	5.00×10^-10
NPC1L1
rs217386	A/G	0.41	-0.036 (-0.044, -0.029)	1.20×10^-19
rs7791240	T/C	0.91	-0.043 (-0.055, -0.030)	1.84×10^-10
rs2073547	A/G	0.81	-0.049 (-0.058, -0.039)	1.92×10^-21
rs17655652	C/T	0.29	-0.028 (-0.037, -0.019)	2.18×10^-10
PCSK9
rs11591147	T/G	0.02	-0.497 (-0.532, -0.462)	8.57×10^-143
rs11206510	C/T	0.15	-0.083 (-0.093, -0.073)	2.38×10^-53
rs10493176	G/T	0.11	-0.078 (-0.098, -0.058)	2.54×10^-14
rs2479409	A/G	0.67	-0.064 (-0.072, -0.056)	2.51×10^-50
rs2495477	G/A	0.40	-0.064 (-0.075, -0.053)	7.28×10^-30
rs2479394	A/G	0.72	-0.039 (-0.047, -0.031)	1.58×10^-19
rs572512	C/T	0.65	-0.048 (-0.057, -0.039)	5.31×10^-26
rs11206514	C/A	0.39	-0.051 (-0.059, -0.043)	9.95×10^-33
rs585131	C/T	0.18	-0.064 (-0.074, -0.054)	2.70×10^-35
rs11583974	G/A	0.97	-0.065 (-0.088, -0.042)	3.95×10^-09
rs12067569	G/A	0.97	-0.089 (-0.108, -0.069)	1.97×10^-17

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