Genetic insights into cholesteryl ester transfer protein as a novel therapeutic target for sepsis and severe pneumonia

Background Lipoproteins were associated with sepsis related mortality because of their critical role in immune-inflammatory modulation and pathogen sequestration. Cholesteryl ester transfer protein (CETP), a lipid-modifying drug target, was reported to be associated with sepsis in recent animal models. However, whether there was a causal effect of inhibition of CETP on reducing the risk of sepsis and severe pneumonia for patients in critical care being still unknown. Therefore, we estimated the causal association of genetically proxied inhibition of CETP, along with high-density and low-density lipoprotein cholesterol directly, with the risk of sepsis, pneumonia and 28-day mortality in critical care. Methods The genotype of sepsis and pneumonia cohorts (N 431,365) were obtained from multi-center biobanks throughout the United Kingdom between 2006 and 2010. Single-nucleotide polymorphisms (SNPs) in CETP associated with circulating high-density lipoprotein cholesterol in a genome-wide association study (GWAS) (N 188,577) were used to proxy inhibition of CETP. We also conducted genetically proxied other three commonly lipid-modifying drug targets (3-hydroxy-3-methylglutaryl coenzyme A reductase, proprotein convertase subtilisin/kexin type 9, and Niemann-Pick C1-Like 1) using a similar method. A drug-target Mendelian randomization framework with inverse-variance weighted method was used to assess the causal association. Results Genetically proxied inhibition of CETP was significantly associated with lower risk of sepsis (odds ratio [OR], 0.83 [95% CI, 0.73–0.95]; P = 0.005), pneumonia (OR, 0.78 [95% CI, 0.72–0.86]; P = 1.46e-07) and lower 28-day mortality from sepsis in critical care (OR, 0.68 [95% CI, 0.52–0.87]; P = 0.003). There was no significant evidence of direct association of genetically proxied high-density and low-density lipoprotein cholesterol levels, and other commonly lipid-modifying drug targets with sepsis, pneumonia and 28-day mortality in critical care. Conclusion Our findings support a causal effect of genetically proxied inhibition of CETP on lower risk of sepsis, severe pneumonia, and sepsis related mortality in critical care. This effect seems to be mechanism-specific, independent of circulating high-density lipoprotein cholesterol levels. However, whether pharmaceutical CETP inhibitors could be a promising strategy for sepsis prevention and treatment remained further clinical trials.