👤 Lisanne L Blauw

We analyzed the effects of the common BMI-increasing melanocortin 4 receptor (MC4R) rs17782313-C allele with a minor allele frequency of 0.22-0.25 on (1) cardiovascular disease outcomes in two large population-based cohorts (Copenhagen City Heart Study and Copenhagen General Population Study, Show less

The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. We examined the effect of a gain-of-function variant in A fixed-effect meta-analysis of all 7 cohorts found that the Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. Show less

Raising HDL using cholesteryl ester transfer protein (CETP) inhibitors failed to show a clinically relevant risk reduction of cardiovascular disease in clinical trials, inviting reconsideration of the role of CETP and HDL in human physiology. Based on solid evidence from studies with isolated macrophages, rodents, and humans, we propose that a major function of CETP may be to modulate HDL in order to help resolve bacterial infections. When gram-negative bacteria invade the blood, as occurs in sepsis, Kupffer cells lose their expression of CETP to increase HDL levels. This rise in HDL prevents systemic endotoxemia by binding lipopolysaccharide and induces a systemic proinflammatory response in macrophages to mediate bacterial clearance. This raises the interesting possibility to repurpose CETP inhibitors for the treatment of sepsis. Show less

Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (β: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (β: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (β: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (β: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318). Show less

According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (µg/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 × 10 Show less

High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown. We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis. We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203). We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777-A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival. Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis. Show less

We recently showed that plasma cholesteryl ester transfer protein (CETP) is mainly derived from VSIG4-positive Kupffer cells. Activation of these cells by the bacterial endotoxin lipopolysaccharide (LPS) strongly decreases CETP expression. As Kupffer cell activation plays a detrimental role in the progression of non-alcoholic fatty liver disease (NAFLD), we aimed to study if metabolic liver inflammation is also associated with a decrease in hepatic and circulating CETP. We collected plasma and liver biopsy samples at various stages of NAFLD from 93 obese individuals who underwent bariatric surgery. Liver lobular inflammation was histologically determined, and liver CETP expression, CETP positive cells, circulating CETP concentrations, and liver VSIG4 expression were quantified. Mean (SD) plasma CETP concentration was 2.68 (0.89) μg/mL. In the presence of liver inflammation, compared to the absence of pathology, the difference in hepatic CETP expression was -0.03 arbitrary units (95% CI -0.26, 0.20), the difference in number of hepatic CETP positive cells (range 11-140 per mm We found no strong evidence for a strong negative association between metabolic liver inflammation and CETP-related outcomes in obese individuals, although we observed consistent trends. These data indicate that metabolic liver inflammation does not mimic the strong effects of LPS on the hepatic expression and production of CETP by Kupffer cells. Show less

We aimed to identify independent genetic determinants of circulating CETP (cholesteryl ester transfer protein) to assess causal effects of variation in CETP concentration on circulating lipid concentrations and cardiovascular disease risk. A genome-wide association discovery and replication study on serum CETP concentration were embedded in the NEO study (Netherlands Epidemiology of Obesity). Based on the independent identified variants, Mendelian randomization was conducted on serum lipids (NEO study) and coronary artery disease (CAD; CARDIoGRAMplusC4D consortium). In the discovery analysis (n=4248), we identified 3 independent variants ( This is the first genome-wide association study identifying independent variants that largely determine CETP concentration. Although high-density lipoprotein cholesterol is not a causal risk factor for CAD, it has been unequivocally demonstrated that low-density lipoprotein cholesterol lowering is proportionally associated with a lower CAD risk. Therefore, the results of our study are fully consistent with the notion that CETP concentration is causally associated with CAD through low-density lipoprotein cholesterol. Show less

Several trials to prevent cardiovascular disease by inhibiting cholesteryl ester transfer protein (CETP) have failed, except Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. Thus far, it is unclear to what extent CETP is causally related to measures of atherosclerosis. The aim of the article was to study the causal relationship between genetically determined CETP concentration and carotid intima-media thickness (cIMT) in a population-based cohort study. In the Netherlands Epidemiology of Obesity study, participants were genotyped, and cIMT was measured by ultrasonography. We examined the relation between a weighted genetic risk score for CETP concentration, based on 3 single-nucleotide polymorphisms that have previously been shown to largely determine CETP concentration and cIMT using Mendelian randomization in the total population and in strata by sex, Framingham 10-year risk, (pre)diabetes, high-density lipoprotein cholesterol, triglycerides, and statin use. We analyzed 5655 participants (56% women) with a mean age of 56 (range 44-66) years, body mass index of 26 (range 17-61) kg/m In this population-based study, there was no causal relation between genetically determined CETP concentration and cIMT in the total population although we observed directionally differing effects in men and women. Stratified results suggested associations in individuals with different cardiometabolic risk factor profiles, which require replication. Show less