Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases low-density lipoprotein apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial.

BACKGROUND: The substitution of monounsaturated acids (MUFAs) for saturated fatty acids (SFAs) is recommended for cardiovascular disease prevention but its impact on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains largely unknown. OBJECTIVES: This study aimed to evaluate the impact of substituting MUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo)B-containing lipoproteins and on the plasma lipidomic profile in adults with IR-induced dyslipidemia. METHODS: Males and females with dyslipidemia associated with IR (n = 18) were recruited for this crossover double-blind randomized controlled trial. Subjects consumed, in random order, a diet rich in SFAs (SFAs: 13.4%E; MUFAs: 14.4%E) and a diet rich in MUFAs (SFAs: 7.1%E; MUFAs: 20.7%E) in fully controlled feeding conditions for periods of 4 wk each, separated by a 4-wk washout. At the end of each diet, fasting plasma samples were taken together with measurements of the in vivo kinetics of apoB-containing lipoproteins. RESULTS: Substituting MUFAs for SFAs had no impact on triglyceride-rich lipoprotein apoB-48 fractional catabolic rate (FCR) (Δ = -8.9%, P = 0.4) and production rate (Δ = 0.0%, P = 0.9), although it decreased very low-density lipoprotein apoB-100 pool size (PS) (Δ = -22.5%; P = 0.01). This substitution also reduced low-density lipoprotein cholesterol (LDL-C) (Δ = -7.0%; P = 0.01), non-high-density lipoprotein cholesterol (Δ = -2.5%; P = 0.04), and LDL apoB-100 PS (Δ = -6.0%; P = 0.05). These differences were partially attributed to an increase in LDL apoB-100 FCR (Δ = +1.6%; P = 0.05). The MUFA diet showed reduced sphingolipid concentrations and elevated glycerophospholipid levels compared with the SFA diet. CONCLUSIONS: This study demonstrated that substituting dietary MUFAs for SFAs decreases LDL-C levels and LDL PS by increasing LDL apoB-100 FCR and results in an overall improved plasma lipidomic profile in individuals with IR-induced lipidemia. TRIAL REGISTRATION: This trial was registered as clinicaltrials.gov as NCT03872349.

Corrigendum: Revisiting multi-omics-based predictors of the plasma triglyceride response to an omega-3 fatty acid supplementation.

[This corrects the article DOI: 10.3389/fnut.2024.1327863.].

Revisiting multi-omics-based predictors of the plasma triglyceride response to an omega-3 fatty acid supplementation.

Background: The aim of the present study was to identify the metabolomic signature of responders and non-responders to an omega-3 fatty acid (n-3 FA) supplementation, and to test the ability of a multi-omics classifier combining genomic, lipidomic, and metabolomic features to discriminate plasma triglyceride (TG) response phenotypes. Methods: A total of 208 participants of the Fatty Acid Sensor (FAS). Study took 5 g per day of fish oil, providing 1.9-2.2 g eicosapentaenoic acid (EPA) and 1.1 g docosahexaenoic (DHA) daily over a 6-week period, and were further divided into two subgroups: responders and non-responders, according to the change in plasma TG levels after the supplementation. Changes in plasma levels of 6 short-chain fatty acids (SCFA) and 25 bile acids (BA) during the intervention were compared between subgroups using a linear mixed model, and the impact of SCFAs and BAs on the TG response was tested in a mediation analysis. Genotyping was conducted using the Illumina Human Omni-5 Quad BeadChip. Mass spectrometry was used to quantify plasma TG and cholesterol esters levels, as well as plasma SCFA and BA levels. A classifier was developed and tested within the DIABLO framework, which implements a partial least squares-discriminant analysis to multi-omics analysis. Different classifiers were developed by combining data from genomics, lipidomics, and metabolomics. Results: Plasma levels of none of the SCFAs or BAs measured before and after the n-3 FA supplementation were significantly different between responders and non-responders. SCFAs but not BAs were marginally relevant in the classification of plasma TG responses. A classifier built by adding plasma SCFAs and lipidomic layers to genomic data was able to even the accuracy of 85% shown by the genomic predictor alone. Conclusion: These results inform on the marginal relevance of SCFA and BA plasma levels as surrogate measures of gut microbiome in the assessment of the interindividual variability observed in the plasma TG response to an n-3 FA supplementation. Genomic data still represent the best predictor of plasma TG response, and the inclusion of metabolomic data added little to the ability to discriminate the plasma TG response phenotypes.

Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Relationship between lifestyle habits and cardiovascular risk factors in familial hypercholesterolemia.

BACKGROUND AND AIM: Little is known about the cardioprotective potential of a healthy lifestyle in familial hypercholesterolemia (FH). The objective of this study was to evaluate the relationship between lifestyle and cardiovascular risk factors in adults with FH. METHODS AND RESULTS: This cross-sectional study leveraged data from the CARTaGENE Quebec population-based cohort (Canada). Participants with FH were identified using the validated Simplified Canadian Definition for FH. A healthy lifestyle score (HLS), ranging from 0 to 5, was calculated per adherence to 5 lifestyle habits: 1) not smoking; 2) being physically active (≥150 min/week of moderate or vigorous physical activity); 3) eating a healthy diet (Alternate Healthy Eating Index ≥50%); 4) having a light to moderate alcohol consumption (men: 1-30 g/day; women: 1-15 g/day); and 5) sleeping 7-8 h/day. Among the 122 included individuals (women, n = 78; men, n = 44; mean age ± SD: 57.3 ± 6.7 years), 92 (75.4%) had a HLS ≤3/5, while only 5 (4.1%) had a HLS of 5/5. After adjustments for sex, age, body mass index, and lipid-lowering medication use, we found no evidence of an association between the HLS and concentrations of LDL-cholesterol (ß = 0.04, 95% CI = -0.08, 0.15 mmol/L; P = 0.54). However, the HLS was favorably associated with HbA1c levels (ß = -0.07, 95% CI = -0.13, -0.01%; P = 0.02), and statistical trends suggested favorable associations with HDL-cholesterol (ß = 0.06, 95% CI = -0.02, 0.14 mmol/L; P = 0.06) and waist circumference (ß = -2.22, 95% CI = -4.62, 0.17 cm; P = 0.07). CONCLUSION: This study suggests that a healthy lifestyle is favorably associated with CVD risk factors in adults with FH.

A discriminant analysis of plasma metabolomics for the assessment of metabolic responsiveness to red raspberry consumption.

Background: Many studies show that the intake of raspberries is beneficial to immune-metabolic health, but the responses of individuals are heterogeneous and not fully understood. Methods: In a two-arm parallel-group, randomized, controlled trial, immune-metabolic outcomes and plasma metabolite levels were analyzed before and after an 8-week red raspberry consumption. Based on partial least squares discriminant analysis (PLS-DA) on plasma xenobiotic levels, adherence to the intervention was first evaluated. A second PLS-DA followed by hierarchical clustering was used to classify individuals into response subgroups. Clinical immune and metabolic outcomes, including insulin resistance (HOMA-IR) and sensitivity (Matsuda, QUICKI) indices, during the intervention were assessed and compared between response subgroups. Results: Two subgroups of participants, type 1 responders (n = 17) and type 2 responders (n = 5), were identified based on plasma metabolite levels measured during the intervention. Type 1 responders showed neutral to negative effects on immune-metabolic clinical parameters after raspberry consumption, and type 2 responders showed positive effects on the same parameters. Changes in waist circumference, waist-to-hip ratio, fasting plasma apolipoprotein B, C-reactive protein and insulin levels as well as Matsuda, HOMA-IR and QUICKI were significantly different between the two response subgroups. A deleterious effect of two carotenoid metabolites was also observed in type 1 responders but these variables were significantly associated with beneficial changes in the QUICKI index and in fasting insulin levels in type 2 responders. Increased 3-ureidopropionate levels were associated with a decrease in the Matsuda index in type 2 responders, suggesting that this metabolite is associated with a decrease in insulin sensitivity for those subjects, whereas the opposite was observed for type 1 responders. Conclusion: The beneficial effects associated with red raspberry consumption are subject to inter-individual variability. Metabolomics-based clustering appears to be an effective way to assess adherence to a nutritional intervention and to classify individuals according to their immune-metabolic responsiveness to the intervention. This approach may be replicated in future studies to provide a better understanding of how interindividual variability impacts the effects of nutritional interventions on immune-metabolic health.

Update of a Genetic Risk Score Predictive of the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation in the FAS Study.

A genetic risk score (GRS) predictive of the plasma triglyceride (TG) response to an omega-3 fatty acid (n-3 FA) supplementation has been previously developed in the Fatty Acid Sensor (FAS) Study. Recently, novel single nucleotide polymorphisms (SNPs) interacting with a fish oil supplementation and associated with plasma lipid levels have been identified in the UK Biobank. The aim of this study was to verify whether the addition of SNPs identified in the UK Biobank to the GRS built in the FAS Study improves its capacity to predict the plasma TG response to an n-3 FA supplementation. SNPs interacting with fish oil supplementation in the modulation of plasma lipid levels in the UK Biobank and associated with plasma TG levels have been genotyped in participants of the FAS Study (n = 141). Participants have been supplemented with 5 g fish oil/day for six weeks. Plasma TG concentrations were measured before and after the supplementation. Based on the initial GRS of 31 SNPs (GRS31), we computed three new GRSs by adding new SNPs identified in the UK Biobank: GRS32 (rs55707100), GRS38 (seven new SNPs specifically associated with plasma TG levels), and GRS46 (all 15 new SNPs associated with plasma lipid levels). The initial GRS31 explained 50.1% of the variance in plasma TG levels during the intervention, whereas GRS32, GRS38, and GRS46 explained 49.1%, 45.9%, and 45%, respectively. A significant impact on the probability of being classified as a responder or a nonresponder was found for each of the GRSs analyzed, but none of them outperformed the predictive capacity of GRS31 in any of the metrics analyzed, i.e., accuracy, area under the response operating curve (AUC-ROC), sensitivity, specificity and McFadden's pseudo R2. The addition of SNPs identified in the UK Biobank to the initial GRS31 did not significantly improve its capacity to predict the plasma TG response to an n-3 FA supplementation. Thus, GRS31 still remains the most precise tool so far by which to discriminate the individual responsiveness to n-3 FAs. Further studies are needed in the field to increase our knowledge of factors underlying the heterogeneity observed in the metabolic response to an n-3 FA supplementation.

Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk.

In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol. Since then, the evidence has continued to mount in favor of apoB. This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk attributable to the atherogenic apoB lipoprotein particles chylomicron remnants, very low-density lipoprotein, and low-density lipoprotein particles. First, the nature and relative numbers of these different apoB particles will be outlined. This will make clear why low-density lipoprotein particles are almost always the major determinants of cardiovascular risk and why the concentrations of triglycerides and LDL-C may obscure this relation. Next, the mechanisms that govern the number of very low-density lipoprotein and low-density lipoprotein particles will be outlined because, except for dysbetalipoproteinemia, the total number of apoB particles determines cardiovascular risk, Then, the mechanisms that govern the cholesterol mass within very low-density lipoprotein and low-density lipoprotein particles will be reviewed because these are responsible for the discordance between the mass of cholesterol within apoB particles, measured either as LDL-C or non-high-density lipoprotein cholesterol, and the number of apoB particles measured as apoB, which creates the superior predictive power of apoB over LDL-C and non-high-density lipoprotein cholesterol. Finally, the major apoB dyslipoproteinemias will be briefly outlined. Our objective is to provide a physiological framework for health care givers to understand why apoB is a more accurate marker of cardiovascular risk than LDL-C or non-high-density lipoprotein cholesterol.

Associations between insulin-like growth factor binding protein-2 and lipoprotein kinetics in men.

Low circulating concentrations of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with dyslipidemia, notably with high triglyceride (TG) levels. However, the determinants by which IGFBP-2 influences lipoprotein metabolism, especially that of TG-rich lipoproteins (TRLs), are poorly understood. Here, we aimed to assess the relationships between IGFBP-2 levels and lipoprotein production and catabolism in human subjects. Fasting IGFBP-2 concentrations were measured in the plasma of 219 men pooled from previous lipoprotein kinetics studies. We analyzed production rate and fractional catabolic rates of TRLapoB-48, and LDL-, IDL-, and VLDLapoB-100 by multicompartmental modeling of l-[5,5,5-D3] leucine enrichment data after a 12 h primed constant infusion in individuals kept in a constant nutritional steady state. Subjects had an average BMI of 30 kg/m2, plasma IGFBP-2 levels of 157 ng/ml, and TG of 2.2 mmol/l. After adjustments for age and BMI, IGFBP-2 levels were negatively associated with plasma TG (r = -0.29; P < 0.0001) and positively associated with HDL-cholesterol (r = 0.26; P < 0.0001). In addition, IGFBP-2 levels were positively associated with the fractional catabolic rate of VLDLapoB-100 (r = 0.20; P < 0.01) and IDLapoB-100 (r = 0.19; P < 0.05) and inversely with the production rate of TRLapoB-48 (r = -0.28; P < 0.001). These correlations remained statistically significant after adjustments for age, BMI, and the amount of fat given during the tracer infusion. These findings show that the association between low plasma IGFBP-2 and high TG concentrations could be due to both an impaired clearance of apoB-100-containing VLDL and IDL particles and an increased production of apoB-48-containing chylomicrons. Additional studies are necessary to investigate whether and how IGFBP-2 directly impacts the kinetics of TRL.

Gene expression signatures and cardiometabolic outcomes following 8-week mango consumption in individuals with overweight/obesity.

Background: Little is known about the impact of mango consumption on metabolic pathways assessed by changes in gene expression. Methods: In this single-arm clinical trial, cardiometabolic outcomes and gene expression levels in whole blood samples from 26 men and women were examined at baseline and after 8 weeks of mango consumption and differential gene expression changes were determined. Based on changes in gene expression profiles, partial least squares discriminant analysis followed by hierarchical clustering were used to classify participants into subgroups of response and differences in gene expression changes and in cardiometabolic clinical outcomes following the intervention were tested. Results: Two subgroups of participants were separated based on the resemblance of gene expression profiles in response to the intervention and as responders (n = 8) and non-responders (n = 18). A total of 280 transcripts were significantly up-regulated and 603 transcripts down-regulated following the intervention in responders, as compared to non-responders. Several metabolic pathways, mainly related to oxygen and carbon dioxide transport as well as oxidative stress, were found to be significantly enriched with differentially expressed genes. In addition, significantly beneficial changes in hip and waist circumference, c-reactive protein, HOMA-IR and QUICKI indices were observed in responders vs. non-responders, following the intervention. Conclusion: The impact of mango consumption on cardiometabolic health appears to largely rely on interindividual variability. The novel transcriptomic-based clustering analysis used herein can provide insights for future research focused on unveiling the origins of heterogeneous responses to dietary interventions. Clinical Trial Registration: [clinicaltrials.gov], identifier [NCT03825276].

Cellulosic copper nanoparticles and a hydrogen peroxide-based disinfectant trigger rapid inactivation of pseudoviral particles expressing the Spike protein of SARS-CoV-2, SARS-CoV, and MERS-CoV.

Severe acute respiratory syndrome (SARS) is a viral respiratory infection caused by human coronaviruses that include SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). Although their primary mode of transmission is through contaminated respiratory droplets from infected carriers, the deposition of expelled virus particles onto surfaces and fomites could contribute to viral transmission. Here, we use replication-deficient murine leukemia virus (MLV) pseudoviral particles expressing SARS-CoV-2, SARS-CoV, or MERS-CoV Spike (S) protein on their surface. These surrogates of native coronavirus counterparts serve as a model to analyze the S-mediated entry into target cells. Carboxymethyl cellulose (CMC) nanofibers that are combined with copper (Cu) exhibit strong antimicrobial properties. S-pseudovirions that are exposed to CMC-Cu nanoparticles (30 s) display a dramatic reduction in their ability to infect target Vero E6 cells, with ∼97% less infectivity as compared to untreated pseudovirions. In contrast, addition of the Cu chelator tetrathiomolybdate protects S-pseudovirions from CMC-Cu-mediated inactivation. When S-pseudovirions were treated with a hydrogen peroxide-based disinfectant (denoted SaberTM) used at 1:250 dilution, their infectivity was dramatically reduced by ∼98%. However, the combined use of SaberTM and CMC-Cu is the most effective approach to restrict infectivity of SARS-CoV-2-S, SARS-CoV-S, and MERS-CoV-S pseudovirions in Vero E6 cell assays. Together, these results show that cellulosic Cu nanoparticles enhance the effectiveness of diluted SaberTM sanitizer, setting up an improved strategy to lower the risk of surface- and fomite-mediated transmission of enveloped respiratory viruses.

Changes in systolic blood pressure, postprandial glucose, and gut microbial composition following mango consumption in individuals with overweight and obesity.

This study aimed to explore the impact of daily mango consumption (Mangifera indica) on cardiometabolic health and gut microbiota in individuals with overweight and obesity. Changes in cardiometabolic variables, gut microbiota diversity and composition, physical activity habits, and dietary intakes were assessed in 8 males and 19 females with overweight and obesity who consumed 280 g/day of mango pulp for 8 weeks. There were no significant changes in body weight, waist circumference, or plasma lipid levels. However, after consuming mangos for 8 weeks, participants showed a 3.5% reduction in systolic blood pressure (-4 ± 6 mm Hg, p = 0.011) as well as a 10.5% reduction in 2-hour plasma glucose concentration after a 75-g oral glucose tolerance test (-0.58 ± 1.03 mmol/L, p = 0.008). These beneficial cardiometabolic outcomes were accompanied with enhanced gut microbiota diversity and with changes in the abundance of specific gut bacterial species. Mango consumption may have beneficial effects on both blood pressure and glucose homeostasis in individuals with overweight and obesity. Further studies are warranted to determine the impact of long-term and regular mango intake on cardiometabolic risk factors of individuals with overweight and obesity, and the potential mechanisms linking gut microbial changes to those health benefits. This study was registered with clinicaltrials.gov as NCT03825276. Novelty: A 3.5% reduction in systolic blood pressure is noted after consuming mangos for 8 weeks. A 10.5% reduction in 2-hour plasma glucose concentration of an oral glucose tolerance test is observed after consuming mangos for 8 weeks. Mango consumption for 8 weeks may enhance gut microbial diversity and abundance of specific bacterial species.

Gut Microbial Signatures of Distinct Trimethylamine N-Oxide Response to Raspberry Consumption.

The aim of this exploratory study was to evaluate the gut microbial signatures of distinct trimethylamine N-oxide (TMAO) responses following raspberry consumption. Investigations were carried out in 24 subjects at risk of developing metabolic syndrome who received 280 g/day of frozen raspberries for 8 weeks. Blood and stool samples were collected at weeks 0 and 8. Inter-individual variability in plasma TMAO levels was analyzed, 7 subjects were excluded due to noninformative signals and 17 subjects were kept for analysis and further stratified according to their TMAO response. Whole-metagenome shotgun sequencing analysis was used to determine the impact of raspberry consumption on gut microbial composition. Before the intervention, the relative abundance of Actinobacteriota was significantly higher in participants whose TMAO levels increased after the intervention (p = 0.03). The delta TMAO (absolute differences of baseline and week 8 levels) was positively associated with the abundance of gut bacteria such as Bilophila wadsworthia (p = 0.02; r2 = 0.37), from the genus Granulicatella (p = 0.03; r2 = 0.48) or the Erysipelotrichia class (p = 0.03; r2 = 0.45). Changes in the gut microbial ecology induced by raspberry consumption over an 8-week period presumably impacted quaternary amines-utilizing activity and thus plasma TMAO levels.

Raspberry consumption: identification of distinct immune-metabolic response profiles by whole blood transcriptome profiling.

Numerous studies have reported that diets rich in phenolic compounds are beneficial to immune-metabolic health, yet these effects are heterogeneous and the underlying mechanisms are poorly understood. To investigate the inter-individual variability of the immune-metabolic response to raspberry consumption, whole-blood RNAseq data from 24 participants receiving 280 g/d of raspberries for 8 weeks were used for the identification of responsiveness subgroups by using partial least squares-discriminant analysis (PLSDA) and hierarchical clustering. Transcriptomic-based clustering regrouped participants into two distinct subgroups of 13 and 11 participants, so-called responders and non-responders, respectively. Following raspberry consumption, a significant decrease in triglycerides, cholesterol and C-reactive protein levels were found in responders, as compared to non-responders. Two major gene expression components of 100 and 220 genes were identified by sparse PLSDA as those better discriminating responders from non-responders, and functional analysis identified pathways related to cytokine production, leukocyte activation and immune response as significantly enriched with most discriminant genes. As compared to non-responders, the plasma lipidomic profile of responders was characterized by a significant decrease in triglycerides and an increase in phosphatidylcholines following raspberry consumption. Prior to the intervention, a distinct metagenomic profile was identified by PLSDA between responsiveness subgroups, and the Firmicutes-to-Bacteroidota ratio was found significantly lower in responders, as compared to non-responders. Findings point to this transcriptomic-based clustering approach as a suitable tool to identify distinct responsiveness subgroups to raspberry consumption. This approach represents a promising framework to tackle the issue of inter-individual variability in the understanding of the impact of foods on immune-metabolic health.

Polymorphisms in the stearoyl-CoA desaturase gene modify blood glucose response to dietary oils varying in MUFA content in adults with obesity.

Diets varying in SFA and MUFA content can impact glycaemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomised, crossover, isoenergetic, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed three dietary oils for 6 weeks, with washout periods of ˜6 weeks between each treatment. Diets studied included a high SFA/low MUFA Control oil (36·6 % SFA/28·2 % MUFA), a conventional canola oil (6·2 % SFA/63·1 % MUFA) and a high-oleic acid canola oil (5·8 % SFA/74·7 % MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (P = 0·01), rs3071 (P = 0·02) and rs522951 (P = 0·03). The interaction for rs3071 remained significant (P = 0·005) when analysed with a recessive model, where individuals carrying the CC genotype showed an increase (0·14 (sem 0·09) mmol/l) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all three oils. These findings identify a potential new target for personalised nutrition approaches aimed at improving glycaemic control.

Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry.

BACKGROUND: Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH. METHODS: A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n = 226; receptor-negative [RN] genotype: n = 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models. RESULTS: There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P = 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P = 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN: -31.1% (95% CI -34.7% to -27.4) vs RD -36.5% (95% CI -40.4% to -32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R2 = 2.3%; P = 0.0001). CONCLUSION: The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.

An 8-week freeze-dried blueberry supplement impacts immune-related pathways: a randomized, double-blind placebo-controlled trial.

BACKGROUND: Blueberries contain high levels of polyphenolic compounds with high in vitro antioxidant capacities. Their consumption has been associated with improved vascular and metabolic health. PURPOSE: The objective was to examine the effects of blueberry supplement consumption on metabolic syndrome (MetS) parameters and potential underlying mechanisms of action. METHODS: A randomized double-blind placebo-controlled intervention trial was conducted in adults at risk of developing MetS. Participants consumed 50 g daily of either a freeze-dried highbush blueberry powder (BBP) or a placebo powder for 8 weeks (n = 49). MetS phenotypes were assessed at weeks 0, 4 and 8. Fasting blood gene expression profiles and plasma metabolomic profiles were examined at baseline and week 8 to assess metabolic changes occurring in response to the BBP. A per-protocol analysis was used. RESULTS: A significant treatment effect was observed for plasma triglyceride levels that was no longer significant after further adjustments for age, sex, BMI and baseline values. In addition, the treatment*time interactions were non-significant therefore suggesting that compared with the placebo, BBP had no statistically significant effect on body weight, blood pressure, fasting plasma lipid, insulin and glucose levels, insulin resistance (or sensitivity) or glycated hemoglobin concentrations. There were significant changes in the expression of 49 genes and in the abundance of 35 metabolites following BBP consumption. Differentially regulated genes were clustered in immune-related pathways. CONCLUSION: An 8-week BBP intervention did not significantly improve traditional markers of cardiometabolic health in adults at risk of developing MetS. However, changes in gene expression and metabolite abundance suggest that clinically significant cardiometabolic changes could take longer than 8 weeks to present and/or could result from whole blueberry consumption or a higher dosage. BBP may also have an effect on factors such as immunity even within a shorter 8-week timeframe. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, NCT03266055 , 2017.

A Comparative Analysis of the Lipoprotein(a) and Low-Density Lipoprotein Proteomic Profiles Combining Mass Spectrometry and Mendelian Randomization.

BACKGROUND: Lipoprotein(a) (Lp[a]), which consists of a low-density lipoprotein (LDL) bound to apolipoprotein(a), is one of the strongest genetic risk factors for atherosclerotic cardiovascular diseases. Few studies have performed hypothesis-free direct comparisons of the Lp(a) and the LDL proteomes. Our objectives were to compare the Lp(a) and the LDL proteomic profiles and to evaluate the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile. METHODS: We performed a label-free analysis of the Lp(a) and LDL proteomic profiles of healthy volunteers in a discovery (n = 6) and a replication (n = 9) phase. We performed inverse variance weighted Mendelian randomization to document the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile of participants of the INTERVAL study. RESULTS: We identified 15 proteins that were more abundant on Lp(a) compared with LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1, and ttr). We found no proteins that were more abundant on LDL compared with Lp(a). After correction for multiple testing, lifelong exposure to elevated LDL cholesterol levels was associated with the variation of 18 plasma proteins whereas Lp(a) did not appear to influence the plasma proteome. CONCLUSIONS: Results of this study highlight marked differences in the proteome of Lp(a) and LDL as well as in the effect of lifelong exposure to elevated LDL cholesterol or Lp(a) on the plasma proteomic profile.

CONTEXTE: La lipoprotéine(a) (Lp[a]), qui est constituée d'une lipoprotéine de basse densité (LDL) liée à une apolipoprotéine(a), est l'un des plus importants facteurs de risque génétiques de survenue d'une maladie cardiovasculaire athéroscléreuse. Peu d'études comparatives directes sans hypothèse ont porté sur le protéome de la Lp(a) et celui des LDL. Nos objectifs étaient de comparer les profils protéomiques de la Lp(a) et des LDL et d'évaluer l'effet d'une exposition à vie à un taux élevé de Lp(a) ou de cholestérol LDL sur le profil protéomique plasmatique. MÉTHODOLOGIE: Nous avons réalisé une analyse sans marquage des profils protéomiques de la Lp(a) et des LDL chez des volontaires en bonne santé dans le cadre d'une phase de découverte (n = 6) et d'une phase de réplication (n = 9). Pour rendre compte de l'effet d'une exposition à vie à un taux élevé de Lp(a) ou de cholestérol des LDL sur le profil protéomique plasmatique des participants de l'étude INTERVAL, nous avons utilisé une analyse de randomisation Mendélienne avec pondération par l'inverse de la variance. RÉSULTATS: Nous avons relevé 15 protéines associées en plus grande abondance à la Lp(a) qu'aux LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1 et ttr). Nous n'avons noté aucune protéine associée en plus grande abondance aux LDL qu'à la Lp(a). Après correction pour tenir compte de la multiplicité des tests, l'exposition à vie à un taux élevé de cholestérol LDL a été associée à la variation de 18 protéines plasmatiques, tandis que le taux de Lp(a) ne semblait pas influencer le protéome plasmatique. CONCLUSIONS: Les résultats de notre étude font ressortir les différences marquées entre le protéome de la Lp(a) et celui des LDL, ainsi qu'entre l'effet sur le profil protéomique plasmatique de l'exposition à vie à un taux élevé de cholestérol LDL et celui de l'exposition à vie à un taux élevé de Lp(a).

A combination of single nucleotide polymorphisms is associated with the interindividual variability in the blood lipid response to dietary fatty acid consumption in a randomized clinical trial.

BACKGROUND: Blood lipid concentrations display high interindividual variability in response to dietary interventions, partly due to genetic factors. Existing studies have focused on single nucleotide polymorphisms (SNPs) analyzed individually, which only explain a limited fraction of the variability of these complex phenotypes. OBJECTIVE: We aimed to identify combinations of SNPs associated with the variability in LDL cholesterol and triglyceride (TG) concentration changes following 5 dietary interventions. DESIGN: In a multicenter randomized crossover trial, 92 participants with elevated waist circumference and low HDL cholesterol concentrations consumed 5 isoenergetic diets for 4 wk: a diet rich in saturated fatty acids (SFAs) from cheese, SFA from butter, monounsaturated fatty acids (MUFAs), n-6 polyunsaturated fatty acids (PUFAs), and a diet higher in carbohydrates (CHO). The association between 22 candidate SNPs in genes involved in lipid and bile acid metabolism and transport and changes in LDL cholesterol and TG concentrations was assessed with univariate statistics followed by partial least squares regression. RESULTS: Endpoint LDL cholesterol concentrations were significantly different (cheese: 3.18 ± 0.04, butter: 3.31 ± 0.04, MUFA: 3.00 ± 0.04, PUFA: 2.81 ± 0.04, CHO: 3.11 ± 0.04 mmol/L; P < 0.001) while endpoint TG concentrations were not (P = 0.117). Both displayed consistently elevated interindividual variability following the dietary interventions (CVs of 34.5 ± 2.2% and 55.8 ± 1.8%, respectively). Among the 22 candidate SNPs, only ABCA1-rs2066714 and apolipoprotein E (APOE) isoforms exhibited consistent significant effects, namely on LDL cholesterol concentrations. However, several SNPs were significantly associated with changes in LDL cholesterol and TG concentrations in a diet-specific fashion. Generated multivariate models explained from 16.0 to 33.6% of the interindividual variability in LDL cholesterol concentration changes and from 17.5 to 32.0% of that in TG concentration changes. CONCLUSIONS: We report combinations of SNPs associated with a significant part of the variability in LDL cholesterol and TG concentrations following dietary interventions differing in their fatty acid profiles.