Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile

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 (mu g/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 x 10(-22)) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 x 10(-6)). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n similar to 20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.Peer reviewe

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK-Biobank. The Lifelines, and The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. RESULTS: In the UK-Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. CONCLUSIONS: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans

Metabolic liver inflammation in obesity does not robustly decrease hepatic and circulating CETP

Proteomic

Metabolic liver inflammation in obesity does not robustly decrease hepatic and circulating CETP

Background and aims: 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. Methods: 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. Results: Mean (SD) plasma CETP concentration was 2.68 (0.89) mu g/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(2)) was -20.0 per mm(2) (95% CI -41.6, 1.9), and the difference in plasma CETP was -0.35 mu g/mL (95% CI -0.80, 0.10). Hepatic VSIG4 expression was not associated with liver inflammation (0.00; 95% CI -0.15, 0.15). Conclusions: 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. (C) 2018 The Authors. Published by Elsevier B.V

Triglyceride-lowering LPL alleles combined with LDL-C-lowering alleles are associated with an additively improved lipoprotein profile.

Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower

Genome-wide Association Study of the Postprandial Triglyceride Response Yields Common Genetic Variation in Hepatic Lipase ().

Background - The increase in serum triglyceride (TG) concentrations in response to a meal is considered a risk factor for cardiovascular disease. We aimed to elucidate the genetics of the postprandial TG response through genome-wide association studies (GWAS). Methods - Participants of the Netherlands Epidemiology of Obesity (NEO) study (n=5,630) consumed a liquid mixed meal after an overnight fast. GWAS of fasting and postprandial serum TG at 150 minutes were performed. To identify genetic variation of postprandial TG independent of fasting TG, we calculated the TG response at 150 min by the residuals of a nonlinear regression that predicted TG at 150 min as a function of fasting TG. Association analyses were adjusted for age, sex and principal components in a linear regression model. Next, using as rs7350789-A as a determinant, we performed linear regression analyses on the residuals of the postprandial response of 149 nuclear magnetic resonance (NMR) based metabolite measures. Results - GWAS of fasting TG and postprandial serum TG at 150 min resulted in completely overlapping loci, replicating previous GWAS. From GWAS of the TG response, we identified rs7350789-A (allele frequency=0.36), mapping to hepatic lipase (LIPC), to be associated with a smaller increase in TG concentrations at 150 min (beta= -0.11; p-value=5.1x10-8). GWAS of fasting and postprandial serum TG at 150 minutes were performed. Rs7350789-A was associated with responses of 33 metabolite measures (p-value<1.4x10-3), mainly smaller increases of the TG component in almost all high-density lipoprotein (HDL) sub-particles (HDL-TG), a smaller decrease of HDL diameter and smaller increases of most components of very low density lipoproteins (VLDL) sub-particles. Conclusions - GWAS of the TG response identified a variant near LIPC as a main contributor to postprandial TG metabolism independent of fasting TG concentrations, resulting in smaller increases of HDL-TG and VLDL sub-particles