Abstract | BACKGROUND: METHODS: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal- ligation and puncture model of sepsis. RESULTS: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87). CONCLUSIONS: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.
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Authors | Mark Trinder, Yanan Wang, Christian M Madsen, Tatjana Ponomarev, Lubos Bohunek, Brendan A Daisely, HyeJin Julia Kong, Lisanne L Blauw, Børge G Nordestgaard, Anne Tybjærg-Hansen, Mark M Wurfel, James A Russell, Keith R Walley, Patrick C N Rensen, John H Boyd, Liam R Brunham |
Journal | Circulation
(Circulation)
Vol. 143
Issue 9
Pg. 921-934
(03 02 2021)
ISSN: 1524-4539 [Electronic] United States |
PMID | 33228395
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anticholesteremic Agents
- Apolipoprotein A-I
- Apolipoprotein E3
- CETP protein, human
- Cholesterol Ester Transfer Proteins
- Cholesterol, HDL
- Cytokines
- Oxazolidinones
- anacetrapib
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Topics |
- Animals
- Anticholesteremic Agents
(therapeutic use)
- Apolipoprotein A-I
(blood)
- Apolipoprotein E3
(genetics)
- Cholesterol Ester Transfer Proteins
(antagonists & inhibitors, genetics, metabolism)
- Cholesterol, HDL
(blood)
- Cytokines
(metabolism)
- Disease Models, Animal
- Female
- Gain of Function Mutation
- Humans
- Mice
- Mice, Transgenic
- Oxazolidinones
(therapeutic use)
- Placebo Effect
- Polymorphism, Single Nucleotide
- Risk Factors
- Sepsis
(drug therapy, mortality, pathology)
- Survival Rate
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