Moving forward the Effects of Gene-Diet Interactions on Human Health.

Back in 2010, when we first published data on the in vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet [...].

Genetic Variants Shaping Inter-individual Differences in Response to Dietary Intakes-A Narrative Review of the Case of Vitamins.

Recent advances in the field of nutrigenetics have provided evidence on how genetic variations can impact the individuals' response to dietary intakes. An objective and reliable assessment of dietary exposures should rely on combinations of methodologies including frequency questionnaires, short-term recalls or records, together with biological samples to evaluate markers of intake or status and to identify genetic susceptibilities. In an attempt to present current knowledge on how genetic fingerprints contribute to an individual's nutritional status, we present a review of current literature describing associations between genetic variants and levels of well-established biomarkers of vitamin status in free-living and generally healthy individuals. Based on the outcomes of candidate gene, genome-wide-association studies and meta-analyses thereof, we have identified several single nucleotide polymorphisms (SNPs) involved in the vitamins' metabolic pathways. Polymorphisms in genes encoding proteins involved in vitamin metabolism and transport are reported to have an impact on vitamin D status; while genetic variants of vitamin D receptor were most frequently associated with health outcomes. Genetic variations that can influence vitamin E status include SNPs involved in its uptake and transport, such as in SCAR-B1 gene, and in lipoprotein metabolism. Variants of the genes encoding the sodium-dependent vitamin C transport proteins are greatly associated with the body's status on vitamin C. Regarding the vitamins of the B-complex, special reference is made to the widely studied variant in the MTHFR gene. Methodological attributes of genetic studies that may limit the comparability and interpretability of the findings are also discussed. Our understanding of how genes affect our responses to nutritional triggers will enhance our capacity to evaluate dietary exposure and design personalized nutrition programs to sustain health and prevent disease.

Nutrigenetics and nutrigenomics: ready for clinical use or still a way to go?

Nutritional Genomics or nutrigenetics/nutrigenomics is an emerging area of research aiming to delineate the interplay between nutrients intake and the reciprocal pathologies with the human genome. Coupled with other omics disciplines, such as metabolomics, proteomics and transcriptomics, nutrigenomics aspires to individualize nutrition, reminiscent of pharmacogenomics and the individualization of drug use. Here, we provide an overview of a session focused on nutrigenomics, organized in conjunction with the Panhellenic Bioscientists Association during the First Greek National Personalised Medicine Conference in Athens, Greece on 15 December 2019.

Effect of olive oil phenolic compounds on the expression of blood pressure-related genes in healthy individuals.

PURPOSE: To investigate whether the ingestion of olive oil having different phenolic contents influences the expression of blood pressure-related genes, involved in the renin-angiotensin-aldosterone system, in healthy humans. METHODS: A randomized, double-blind, crossover human trial with 18 healthy subjects, who ingested 25 mL/day of olive oils (1) high (366 mg/kg, HPC) and (2) low (2.7 mg/kg, LPC) in phenolic compounds for 3 weeks, preceded by 2-week washout periods. Determination of selected blood pressure-related gene expression in peripheral blood mononuclear cells (PBMNC) by qPCR, blood pressure and systemic biomarkers. RESULTS: HPC decreased systolic blood pressure compared to pre-intervention values and to LPC, and maintained diastolic blood pressure values compared to LPC. HPC decreased ACE and NR1H2 gene expressions compared with pre-intervention values, and IL8RA gene expression compared with LPC. CONCLUSIONS: The introduction to the diet of an extra-virgin olive oil rich in phenolic compounds modulates the expression of some of the genes related to the renin-angiotensin-aldosterone system. These changes could underlie the decrease in systolic blood pressure observed.

Nutritional Genomics and the Mediterranean Diet's Effects on Human Cardiovascular Health.

The synergies and cumulative effects among different foods and nutrients are what produce the benefits of a healthy dietary pattern. Diets and dietary patterns are a major environmental factor that we are exposed to several times a day. People can learn how to control this behavior in order to promote healthy living and aging, and to prevent diet-related diseases. To date, the traditional Mediterranean diet has been the only well-studied pattern. Stroke incidence, a number of classical risk factors including lipid profile and glycaemia, emergent risk factors such as the length of telomeres, and emotional eating behavior can be affected by genetic predisposition. Adherence to the Mediterranean diet could exert beneficial effects on these risk factors. Our individual genetic make-up should be taken into account to better prevent these traits and their subsequent consequences in cardiovascular disease development. In the present work, we review the results of nutritional genomics explaining the role of the Mediterranean diet in human cardiovascular disease. A multidisciplinary approach is necessary to extract knowledge from large-scale data.

Dietary lipids modulate the expression of miR-107, a miRNA that regulates the circadian system.

SCOPE: The increased prevalence of cardiovascular diseases (CVDs) has been hypothesized to be the result of an increased exposure to a host of atherogenic environmental factors, paramount among them being unhealthy dietary habits. Long-chain n-3 polyunsaturated fatty acids (PUFAs) have been shown to have cardio protective effects, partially due to their ability to regulate gene expression. In this regard, increasing attention has been devoted to the role of miRNAs as regulators of multiple metabolic pathways whose deregulation has been associated with CVD risk. In this work we investigated whether miRNA expression was regulated by docosahexanoic acid, conjugated linoleic acid and cholesterol in Caco-2 cells. RESULTS: Among the modulated miRNAs, miR-107 was differentially expressed by all treatments and this modulation was independent of its hosting gene, panthothenate kinase 1, possibly through its own promoter, which contains binding sites for metabolically relevant transcription factors. Among the putative target genes of miR-107, we found some genes with key roles in circadian rhythm. Specifically, we demonstrated that binding of miR-107 to the circadian locomotor output cycles kaput gene results in the deregulation of the circadian rhythm of the cells. CONCLUSION: Since chronodisruption has been linked to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and CVD, our findings suggest that miR-107 could represent a new approach for pharmacological treatment of these diseases.

Effects of functional olive oil enriched with its own phenolic compounds on endothelial function in hypertensive patients. A randomised controlled trial.

UNLABELLED: The additional health-promoting properties of functional virgin olive oil (FVOO) enriched with its own phenolic compounds (OOPC) versus the parental virgin olive oil (VOO) must be tested in appropriate human clinical trials. Our aim was to assess the effects of FVOO on endothelial function in hypertensive patients. Thirteen pre- and stage-1 hypertensive patients received a single dose of 30 mL of FVOO (OOPC=961 mg/kg) or VOO (OOPC=289 mg/kg) in a postprandial randomised, double blind, crossover trial. Endothelial function, measured as ischemic reactive hyperemia (IRH) and related biomarkers, were followed for 5h after consumption. Compared with VOO, FVOO increased IRH (P<0.05) and plasma Cmax of hydroxytyrosol sulphate, a metabolite of OOPC 2h postprandial (P=0.05). After FVOO ingestion, oxidised LDL decreased (P=0.010) in an inverse relationship with IRH AUC values (P=0.01). FVOO provided more benefits on endothelial function than a standard natural virgin olive oil in pre- and hypertensive patients. TRIAL REGISTRATION: isrctn.org. Identifier ISRCTN03450153.

Dietary lipids modulate the expression of miR-107, an miRNA that regulates the circadian system.

SCOPE: The increased prevalence of cardiovascular diseases (CVDs) has been hypothesized to be the result of an increased exposure to a host of atherogenic environmental factors, paramount among them being unhealthy dietary habits. Long-chain n-3 polyunsaturated fatty acids have been shown to have cardio protective effects, partially due to their ability to regulate gene expression. In this regard, increasing attention has been devoted to the role of miRNAs as regulators of multiple metabolic pathways whose deregulation has been associated with CVD risk. METHODS AND RESULTS: In this work, we investigated whether miRNA expression was regulated by docosahexanoic acid, conjugated linoleic acid, and cholesterol in Caco-2 cells. The modulated miRNAs, miR-107 was differentially expressed by all treatments and this modulation was independent of its hosting gene, PANK1, possibly through its own promoter, which contains binding sites for metabolically relevant transcription factors. Among the putative target genes of miR-107, we found some genes with key roles in circadian rhythm. Specifically, we demonstrated that binding of miR-107 to the CLOCK gene results in the deregulation of the circadian rhythm of the cells. CONCLUSION: Since chronodisruption has been linked to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and CVD, our findings suggests that miR-107 could represent a new approach for pharmacological treatment of these diseases.

Personalized nutrition and cardiovascular disease prevention: From Framingham to PREDIMED.

Diet is considered the cornerstone for the prevention of age-related diseases, and a low-fat diet has been considered for decades as the most suitable alternative to achieve this goal. However, mounting evidence supports the efficacy of other alternatives, such as the Mediterranean diet. Nevertheless, it is well known that people present a dramatic range of responses to similar environmental challenges, and it has been shown that some of this variability is rooted in the genome. In fact, this knowledge is driving the field of nutrigenetics. The finding of interactions between diet and genetic variants has led to intense research and debate about the effectiveness of personalized nutrition as a more suitable tool for the prevention of chronic diseases than the traditional 1-size-fits-all recommendations. Here, we provide some of our own examples that illustrate the progression of nutrigenetics through the years, from the initial studies within the Framingham Heart Study, to the most recent use of large consortia, such as the Cohorts for Heart and Aging Research in Genomic Epidemiology, and ending up with large dietary intervention studies, such as the PREDIMED (Prevención con Dieta Mediterránea) study. These recent approaches are providing more robust and clinically relevant gene-diet interactions. Therefore, although the current evidence level of applying genomic information to tailoring is at its early stages, the prospect of widespread incorporation of nutrigenetics to the clinical practice is encouraging.

Up-to date knowledge on the in vivo transcriptomic effect of the Mediterranean diet in humans.

The present review discusses and summarizes the up-to-date body of knowledge concerning human nutrigenomic studies with Mediterranean diet (MedDiet) and olive oil (OO) interventions, at real-life doses and conditions. A literature review was carried out until March 2012. Original articles assessing the nutrigenomic effect of the MedDiet and its main source of fat, OO, on gene expression were selected. State-of-the-art data in this field, although scarce, are promising. Despite a great diversity among studies, the attributed health benefits of the MedDiet and its components, such as OO, could be explained by a transcriptomic effect on atherosclerosis, inflammation, and oxidative stress-related genes (i.e. ADRB2, IL7R, IFNγ, MCP1, TNFα). Gene expression changes toward a protective mode were often associated with an improvement in systemic markers for oxidation and inflammation. The suggested underlying molecular pathways responsible for these changes, and the extent to which evidence exists of a MedDiet and OO nutrigenomic effect, are also discussed.

Olive oil polyphenols enhance the expression of cholesterol efflux related genes in vivo in humans. A randomized controlled trial.

Both oleic acid and polyphenols have been shown to increase high-density lipoprotein (HDL) cholesterol and to protect HDL from oxidation, a phenomenon associated with a low cholesterol efflux from cells. Our goal was to determine whether polyphenols from olive oil could exert an in vivo nutrigenomic effect on genes related to cholesterol efflux in humans. In a randomized, controlled, cross-over trial, 13 pre/hypertensive patients were assigned 30 ml of two similar olive oils with high (961 mg/kg) and moderate (289 mg/kg) polyphenol content. We found an increase in ATP binding cassette transporter-A1, scavenger receptor class B type 1, peroxisome proliferator-activated receptor (PPAR)BP, PPARα, PPARγ, PPARδ and CD36 gene expression in white blood cells at postprandial after high polyphenol olive oil when compared with moderate polyphenol olive oil intervention (P<.017), with COX-1 reaching borderline significance (P=.024). Linear regression analyses showed that changes in gene expression were related to a decrease in oxidized low-density lipoproteins and with an increase in oxygen radical absorbance capacity and olive oil polyphenols (P<.05). Our results indicate a significant role of olive oil polyphenols in the up-regulation of genes involved in the cholesterol efflux from cells to HDL in vivo in humans. These results are in agreement with previous ones concerning the fact that benefits associated with polyphenol-rich olive oil consumption on cardiovascular risk could be mediated through an in vivo nutrigenomic effect in humans.

Protection of LDL from oxidation by olive oil polyphenols is associated with a downregulation of CD40-ligand expression and its downstream products in vivo in humans.

BACKGROUND: Recently, the European Food Safety Authority approved a claim concerning the benefits of olive oil polyphenols for the protection of LDL from oxidation. Polyphenols could exert health benefits not only by scavenging free radicals but also by modulating gene expression. OBJECTIVE: We assessed whether olive oil polyphenols could modulate the human in vivo expressions of atherosclerosis-related genes in which LDL oxidation is involved. DESIGN: In a randomized, crossover, controlled trial, 18 healthy European volunteers daily received 25 mL olive oil with a low polyphenol content (LPC: 2.7 mg/kg) or a high polyphenol content (HPC: 366 mg/kg) in intervention periods of 3 wk separated by 2-wk washout periods. RESULTS: Systemic LDL oxidation and monocyte chemoattractant protein 1 and the expression of proatherogenic genes in peripheral blood mononuclear cells [ie, CD40 ligand (CD40L), IL-23α subunit p19 (IL23A), adrenergic ß-2 receptor (ADRB2), oxidized LDL (lectin-like) receptor 1 (OLR1), and IL-8 receptor-α (IL8RA)] decreased after the HPC intervention compared with after the LPC intervention. Random-effects linear regression analyses showed 1) a significant decrease in CD40, ADRB2, and IL8RA gene expression with the decrease of LDL oxidation and 2) a significant decrease in intercellular adhesion molecule 1 and OLR1 gene expression with increasing concentrations of tyrosol and hydroxytyrosol in urine. CONCLUSIONS: In addition to reducing LDL oxidation, the intake of polyphenol-rich olive oil reduces CD40L gene expression, its downstream products, and related genes involved in atherogenic and inflammatory processes in vivo in humans. These findings provide evidence that polyphenol-rich olive oil can act through molecular mechanisms to provide cardiovascular health benefits. This trial was registered at www.controlled-trials.com as ISRCTN09220811.

Effect of a traditional Mediterranean diet on apolipoproteins B, A-I, and their ratio: a randomized, controlled trial.

OBJECTIVES: Apolipoprotein (Apo)B, ApoA-I, and their ratio could predict coronary heart disease (CHD) risk more accurately than conventional lipid measurements. Our aim was to assess the effect of a traditional Mediterranean diet (TMD) on apolipoproteins. METHODS: High-cardiovascular risk subjects (n=551, 308 women and 243 men), aged 55-80 years, were recruited into a large, multicenter, randomized, controlled, parallel-group, clinical trial (The PREDIMED Study) aimed at testing the efficacy of TMD on primary cardiovascular disease prevention. Participants assigned to a low-fat diet (control) (n=177), or TMDs (TMD+virgin olive oil (VOO), n=181 or TMD+nuts, n=193) received nutritional education and either free VOO (ad libitum) or nuts (dose: 30 g/day). A 3-month evaluation was performed. RESULTS: Both TMDs promoted beneficial changes on classical cardiovascular risk factors. ApoA-I increased, and ApoB and ApoB/ApoA-I ratio decreased after TMD+VOO, the changes promoting a lower cardiometabolic risk. Changes in TMD+VOO versus low-fat diet were -2.9 mg/dL (95% CI, -5.6 to -0.08), 3.3mg/dL (95% CI, 0.84 to 5.8), and -0.03 mg/dL (-0.05 to -0.01) for ApoB, ApoA-I, and ApoB/ApoA-I ratio, respectively. CONCLUSIONS: Individuals at high-cardiovascular risk who improved their diet toward a TMD pattern rich in virgin olive oil, reduced their Apo B and ApoB/ApoA-I ratio and improved ApoA-I concentrations.

In vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet: a randomized controlled trial.

The aim of the study was to assess whether benefits associated with the traditional Mediterranean diet (TMD) and virgin olive oil (VOO) consumption could be mediated through changes in the expression of atherosclerosis-related genes. A randomized, parallel, controlled clinical trial in healthy volunteers (n=90) aged 20 to 50 yr was performed. Three-month intervention groups were as follows: 1) TMD with VOO (TMD+VOO), 2) TMD with washed virgin olive oil (TMD+WOO), and 3) control with participants' habitual diet. WOO was similar to VOO, but with a lower polyphenol content (55 vs. 328 mg/kg, respectively). TMD consumption decreased plasma oxidative and inflammatory status and the gene expression related with both inflammation [INF-gamma (INFgamma), Rho GTPase-activating protein15 (ARHGAP15), and interleukin-7 receptor (IL7R)] and oxidative stress [adrenergic beta(2)-receptor (ADRB2) and polymerase (DNA-directed) kappa (POLK)] in peripheral blood mononuclear cells. All effects, with the exception of the decrease in POLK expression, were particularly observed when VOO, rich in polyphenols, was present in the TMD dietary pattern. Our results indicate a significant role of olive oil polyphenols in the down-regulation of proatherogenic genes in the context of a TMD. In addition, the benefits associated with a TMD and olive oil polyphenol consumption on cardiovascular risk can be mediated through nutrigenomic effects.

Olive oil and cardiovascular health.

The Mediterranean diet, in which olive oil is the primary source of fat, is associated with a low mortality for cardiovascular disease. Data concerning olive oil consumption and primary end points for cardiovascular disease are scarce. However, a large body of knowledge exists providing evidence of the benefits of olive oil consumption on secondary end points for the disease. Besides the classical benefits on the lipid profile provided by olive oil consumption compared with that of saturated fat, a broad spectrum of benefits on cardiovascular risk factors is now emerging associated with olive oil consumption. We review the state of the art concerning the knowledge of the most important biological and clinical effects related to olive oil and its minor components. The recent advances in human nutrigenomics associated with olive oil consumption will also be assessed. The wide range of benefits associated with olive oil consumption could contribute to explaining the low rate of cardiovascular mortality found in southern European-Mediterranean countries, in comparison with other westernized countries, despite a high prevalence of coronary heart disease risk factors.

Time course of changes in the expression of insulin sensitivity-related genes after an acute load of virgin olive oil.

Our aim was to examine whether an acute fat load could induce changes in the expression of insulin sensitivity-related genes in human peripheral blood mononuclear cells. Selection of candidate genes was based on previous studies with sustained virgin olive oil (VOO) consumption and biological plausibility in relation to insulin sensitivity. Eleven healthy volunteers ingested raw VOO (50 mL). Blood samples were collected at 0, 1 and 6 h. Plasma glucose, insulin and hydroxytyrosol increased at 1 h and decreased at 6 h. Lipid oxidative damage increased at 6 h (p < 0.05). Gene expression changes were characterized based on quantification of the samples relative to a reference sample [i.e., relative quantification (RQ) method]. A 1 h downregulation was observed in O-linked-N-acetylglucosamine transferase (OGT, RQ: 0.62 +/- 0.32) and arachidonate-5-lipoxygenase-activating protein (ALOX5AP, RQ: 0.64 +/- 0.31) genes (p < 0.005). OGT was upregulated at 6 h (RQ: 1.88 +/- 0.28, p < 0.05). CD36 (thrombospondin receptor) was upregulated at 1 h (RQ: 1.6 +/- 0.8, p < 0.05) returning to the basal values at 6 h. Lipoic acid synthetase (LIAS), peroxisome proliferator-activated receptor binding protein (PPARBP), a disintegrin and metallopeptidase domain 17 (ADAM17), and adrenergic beta-2-receptor (ADRB2) genes were upregulated at 6 h (range for the mean RQ: 1.33-1.56) following an increasing linear trend (p < 0.05) from baseline to 6 h. ALOX5AP and OGT genes inversely correlated with insulin and glucose levels at 1 h. ADAM17 and ADRB2 inversely correlated with oxLDL at 6 h (p < 0.05). Taken together, these observations may inform the future clinical nutrigenomics study designs and indicate that a single dose of VOO can elicit quantifiable and rapid changes in gene expression in targets that are mechanistically relevant for insulin sensitivity and the metabolic syndrome.

Mononuclear cell transcriptome response after sustained virgin olive oil consumption in humans: an exploratory nutrigenomics study.

Virgin olive oil (VOO) is considered to be one of the main components responsible for the health benefits of the Mediterranean diet, particularly against atherosclerosis where peripheral blood mononuclear cells (PBMNCs) play a crucial role in atherosclerosis development and progression. The objective of this article was to identify the PBMNC genes that respond to VOO consumption in order to ascertain the molecular mechanisms underlying the beneficial action of VOO in the prevention of atherosclerosis. Gene expression profiles of PBMNCs from healthy individuals were examined in pooled RNA samples by microarrays after 3 weeks of moderate and regular consumption of VOO, as the main fat source in a diet controlled for antioxidant content. Gene expression was verified by qPCR. The response to VOO consumption was confirmed for individual samples (n = 10) by qPCR for 10 upregulated genes (ADAM17, ALDH1A1, BIRC1, ERCC5, LIAS, OGT, PPARBP, TNFSF10, USP48, and XRCC5). Their putative role in the molecular mechanisms involved in atherosclerosis development and progression is discussed, focusing on a possible relation with VOO consumption. Our data support the hypothesis that 3 weeks of nutritional intervention with VOO supplementation, at doses common in the Mediterranean diet, can alter the expression of genes related to atherosclerosis development and progression.