👤 Frits R Rosendaal

Postprandial metabolic impairments play a key role in the pathophysiology of cardiometabolic diseases. While liver fat content has been linked to distinct fasting metabolite profiles, its relationship with postprandial metabolite profiles remains unexplored. In this study, we aimed to (1) examine to what extent liver fat content is associated with the postprandial metabolomic profile beyond fasting metabolites; and (2) investigate whether diet-induced changes in liver fat content are associated with changes in plasma metabolites identified in objective 1. In a subpopulation (n = 1986) of an existing cohort study and a 12-week dietary intervention study (n = 80), liver fat content was measured by proton magnetic resonance spectroscopy and categorized as low (< 2.5%), middle (2.5-5.5%), or high (> 5.5%). In the cohort study, plasma metabolomic profiles were quantified by NMR spectroscopy at fasting (T High liver fat group was characterized by higher fasting and postprandial levels of triglycerides, all VLDL and the small LDL/HDL subclasses, ApoB, fatty acids, glycoprotein acetyls, and BCAAs, and lower medium/larger HDL subclasses, and acetate compared to the low liver fat group. In the high vs. low liver fat group, postprandial responses of cholesterol content of S-LDL, IDL, and S-HDL, glutamine and histidine, omega-3% and DHA % were lower. Diet-induced reductions in liver fat were associated with reductions in 40 fasting plasma metabolites, including VLDL-TG, tyrosine, isoleucine, fatty acid ratios, and most of the VLDL subclasses. Postprandial metabolomic profiling revealed additional associations between liver fat content and plasma metabolites beyond fasting measures, particularly in lipoprotein cholesterol and fatty acid composition. Diet-induced reductions in liver fat were associated with favorable changes in fasting metabolites, but not postprandial metabolite responses. Future studies with harmonized postprandial assessment are needed to further elucidate the postprandial observations and the underlying mechanisms. The trials in this study were registered at clinicaltrials.gov as NL21981.058.08/P08.109 and NCT02194504. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) may progress to liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. So far, genome-wide association studies explain a small fraction of MASLD heritability. We sought to identify novel genetic determinants of MASLD by exploring interactions between genetic variants and body mass index (BMI). First, we examined genome-wide interactions with BMI for circulating alanine aminotransferase (ALT) levels using UK Biobank data. For identified loci, we next examined associations with hepatic proton density fat fraction (PDFF) in 35,146 independent UK Biobank participants. Associations with PDFF were replicated in four independent European cohorts, followed by a phenome-wide association study. Finally, we used human liver epigenomic maps and CRISPR/Cas9 experiments in vitro and in vivo to functionally characterize the CYP7A1 locus. Thirteen loci interact with BMI for ALT (P<5E-8), including eight well-known genetic modulators of MASLD. Two loci-UBXN2B/CYP7A1 and GIPR-are additionally associated with PDFF. For the intronic rs34783010 in GIPR, the minor T allele is associated with lower BMI and higher HbA1c and liver triglyceride content in humans. The UBXN2B/CYP7A1 locus is associated with PDFF in four additional European cohorts. Epigenomic data and in vitro experiments in human liver cells prioritise rs10504255 and CYP7A1 as the functional effectors in this locus. Perturbation of CYP7A1 orthologues using CRISPR/Cas9 results in less liver fat in 10-day-old, metabolically challenged zebrafish larvae. A genome-wide single nucleotide polymorphism×BMI design fuelled identification of two MASLD genes: CYP7A1 and GIPR. Show less

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73-0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention. Show less

Patients with lower-leg cast immobilization and patients undergoing knee arthroscopy have an increased risk of venous thrombosis (VT). Guidelines are ambiguous about thromboprophylaxis use, and individual risk factors for developing VT are often ignored. To assist in VT risk stratification and guide thromboprophylaxis use, various prediction models have been developed. These models depend largely on clinical factors and provide reasonably good C-statistics of around 70%. We explored using protein levels in blood plasma measured by multiplexed quantitative targeted proteomics to predict VT. Our aim was to assess whether a VT risk prediction model based on absolute plasma protein quantification is possible. We used internal standards to quantify proteins in less than 10 μl plasma. We measured 270 proteins in samples from patients scheduled for knee arthroscopy or with lower-leg cast immobilization. The two prospective POT-(K)CAST trails allow complementary views of VT signature in blood, namely pre and post trauma, respectively. From approximately 3000 patients, 31 patients developed VT who were included and matched with double the number of controls. Top discriminating proteins between cases and controls included APOC3, APOC4, APOC2, ATRN, F13B, and F2 in knee arthroscopy patients and APOE, SERPINF2, B2M, F13B, AFM, and C1QC in patients with lower-leg cast. A logistic regression model with cross-validation resulted in C-statistics of 88.1% (95% CI: 85.7-90.6%) and 79.6% (95% CI: 77.2-82.0%) for knee arthroscopy and cast immobilization groups respectively. Promising C-statistics merit further exploration of the value of proteomic tests for predicting VT risk upon additional validation. Show less

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology. Show less

Cholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism. Previous studies have suggested that the CETP TaqI B1/B2 allele is associated with the risk of venous thrombosis (VT). To investigate the associations between genetically determined CETP concentrations and 22 hemostatic factors in healthy individuals, and the risk of a first VT event, in a large VT case-control study. Analyses were performed in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) case-control study. CETP unweighted/weighted genetic risk scores (GRSs) were derived from three single-nucleotide polymorphisms that were identified from a recent genome-wide association study on serum CETP concentrations. The associations between CETP GRSs and 22 hemostatic factors (procoagulant/anticoagulant and fibrinolytic factors) were assessed by linear regression from an additive model in controls (n = 2813). The associations between CETP GRSs and the risk of a first VT were assessed by logistic regression analyses in 3950 VT cases and 4765 controls. In the controls (median age, 49 years; 53% women), both unweighted and weighted GRSs showed that factor VII activity was negatively associated with the genetically determined CETP concentration (weighted GRS β -3.08 IU/dL per μg/mL genetically determined CETP, 95% confidence interval -5.73 to -0.42). No association was observed with the risk of a first VT. Genetically determined CETP concentrations only showed a weak negative association with factor VII activity. However, this did not lead to an association with the risk of a first VT. 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

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

Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10 In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study). Show less