Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study.

AIMS: Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. METHODS AND RESULTS: Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. CONCLUSION: The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.

Long-term dietary adherence and changes in dietary intake in coronary patients after intervention with a Mediterranean diet or a low-fat diet: the CORDIOPREV randomized trial.

PURPOSE: Adherence to a healthy dietary pattern positively influences clinical outcomes in cardiovascular prevention, but long-term adherence is difficult to maintain. We evaluated 5-year changes in dietary habits, adherence achieved, and its maintenance in a cohort of coronary patients from the CORDIOPREV study. METHODS: 1002 coronary patients were randomized to a Mediterranean diet (n = 502) or a low-fat diet (n = 500) and received individual-group-telephone visits and personalized dietary advice. A validated food-frequency questionnaire, a 14-point Mediterranean diet adherence screener, and a 9-point low-fat diet adherence score were used. Dietary adherence was categorized into Low, Medium, and High Adherence. Changes in nutrient intake, food consumption, and adherence were analyzed on a yearly basis. The maintenance of long-term dietary adherence was evaluated using data after the first year and fifth year. RESULTS: From baseline to 5 years, significant increases were observed in overall dietary adherence (Mediterranean diet from 8.9 to 11.4; low-fat diet from 3.9 to 7.1) and in the percentage of patients considered High Adherence (Mediterranean diet from 41 to 89%; low-fat diet from 4 to 67%). When we evaluated the maintenance of adherence, patients considered Low and Medium Adherence at 1 year increased their adherence at the 5 years with both diets and patients considered High Adherence maintained their adherence with a Mediterranean diet, but decreased their adherence with a low-fat diet. CONCLUSIONS: A comprehensive dietary intervention results in an overall long-term improvement and maintenance of adherence to the Mediterranean and low-fat diets. In our population, the Mediterranean diet group achieved a high level of adherence in the short term which was maintained in the long term.

Competitive season effects on polyunsaturated fatty acid content in erythrocyte membranes of female football players.

BACKGROUND: An optimal and correctly balanced metabolic status is essential to improve sports performance in athletes. Recent advances in omic tools, such as the lipid profile of the mature erythrocyte membranes (LPMEM), allow to have a comprehensive vision of the nutritional and metabolic status of these individuals to provide personalized recommendations for nutrients, specifically, the essential omega-3 and omega-6 fatty acids, individuating deficiencies/unbalances that can arise from both habitual diet and sportive activity. This work aimed to study the LPMEM in professional female football players during the football season for the first time and compare it with those defined as optimal values for the general population and a control group. METHODS: An observational study was carried out on female football players from the Athletic Club (Bilbao) playing in the first division of the Spanish league. Blood samples were collected at three points: at the beginning, mid-season, and end of the season for three consecutive seasons (2019-2020, 2020-2021, and 2021-2022), providing a total of 160 samples from 40 women. The LPMEM analysis was obtained by GC-FID by published method and correlated to other individual data, such as blood biochemical parameters, body composition, and age. RESULTS: We observed a significant increase in docosahexaenoic acid (DHA) (p 0.048) and total polyunsaturated fatty acid (PUFA) (p 0.021) in the first season. In the second season, we observed a buildup in the membrane arachidonic acid (AA) (p < .001) and PUFA (p < .001) contents when high training accumulated. In comparison with the benchmark of average population values, 69% of the football players showed lower levels of omega-6 dihomo-γ-linolenic acid (DGLA), whereas 88%, 44%, and 81% of the participants showed increased values of AA, eicosapentaenoic acid (EPA), and the ratio of saturated and monounsaturated fatty acids (SFA/MUFA), respectively. Regarding relationships between blood biochemical parameters, body composition, and age with LPMEM, we observed some mild negative correlations, such as AA and SFA/MUFA ratio with vitamin D levels (coefficient = -0.34 p = .0019 and coefficient = -.25 p = .042); DGLA with urea and cortisol (coefficient = -0.27 p < .006 and coefficient = .28 p < .0028) and AA with age (coefficient = -0.33 p < .001). CONCLUSION: In conclusion, relevant variations in several fatty acids of the membrane fatty acid profile of elite female football players were observed during the competitive season and, in comparison with the general population, increased PUFA contents were confirmed, as reported in other sportive activities, together with the new aspect of DGLA diminution, an omega-6 involved in immune and anti-inflammatory responses. Our results highlight membrane lipidomics as a tool to ascertain the molecular profile of elite female football players with a potential application for future personalized nutritional strategies (diet and supplementation) to address unbalances created during the competitive season.

Unbiased plasma proteomics discovery of biomarkers for improved detection of subclinical atherosclerosis.

BACKGROUND: Imaging of subclinical atherosclerosis improves cardiovascular risk prediction on top of traditional risk factors. However, cardiovascular imaging is not universally available. This work aims to identify circulating proteins that could predict subclinical atherosclerosis. METHODS: Hypothesis-free proteomics was used to analyze plasma from 444 subjects from PESA cohort study (222 with extensive atherosclerosis on imaging, and 222 matched controls) at two timepoints (three years apart) for discovery, and from 350 subjects from AWHS cohort study (175 subjects with extensive atherosclerosis on imaging and 175 matched controls) for external validation. A selected three-protein panel was further validated by immunoturbidimetry in the AWHS population and in 2999 subjects from ILERVAS cohort study. FINDINGS: PIGR, IGHA2, APOA, HPT and HEP2 were associated with subclinical atherosclerosis independently from traditional risk factors at both timepoints in the discovery and validation cohorts. Multivariate analysis rendered a potential three-protein biomarker panel, including IGHA2, APOA and HPT. Immunoturbidimetry confirmed the independent associations of these three proteins with subclinical atherosclerosis in AWHS and ILERVAS. A machine-learning model with these three proteins was able to predict subclinical atherosclerosis in ILERVAS (AUC [95%CI]:0.73 [0.70-0.74], p < 1 × 10-99), and also in the subpopulation of individuals with low cardiovascular risk according to FHS 10-year score (0.71 [0.69-0.73], p < 1 × 10-69). INTERPRETATION: Plasma levels of IGHA2, APOA and HPT are associated with subclinical atherosclerosis independently of traditional risk factors and offers potential to predict this disease. The panel could improve primary prevention strategies in areas where imaging is not available. FUNDING: This study was supported by competitive grants from the Spanish Ministry of Science, Innovation and Universities (BIO2015-67580-P, PGC2018-097019-B-I00, PID2019-106814RB-I00 and SAF2016-80843-R), through the Carlos III Institute of Health-Fondo de Investigacion Sanitaria grant PRB3 (IPT17/0019 - ISCIII-SGEFI / ERDF, ProteoRed), CIBERCV and CIBERDEM, the Fundacio MaratoTV3 (grant 122/C/2015) and "la Caixa" Banking Foundation (project HR17-00247). The PESA study is co-funded equally by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The ILERVAS study was funded by the Diputacio de Lleida. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019; PI18/00610; RD16/0009) and the FEDER funds. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCNU) and the Pro CNIC Foundation.

ABCA1 gene variants regulate postprandial lipid metabolism in healthy men.

OBJECTIVE: Genetic variants of ABCA1, an ATP-binding cassette (ABC) transporter, have been linked to altered atherosclerosis progression and fasting lipid concentration, mainly high-density lipoproteins and apolipoprotein A1; however, results from different studies have been inconsistent. METHODS AND RESULTS: To further characterize the effects of ABCA1 variants in human postprandial lipid metabolism, we studied the influence of 3 single nucleotide polymorphisms (i27943 [rs2575875]; i48168 [rs4149272]; R219K [rs2230806]) in the postprandial lipemia of 88 normolipidemic young men who were given a fatty meal. For i27943 and i48168 single nucleotide polymorphisms, fasting and postprandial values of apolipoprotein A1 were higher and postprandial lipemia was much lower in homozygotes for the major alleles, total triglycerides in plasma, and large triglyceride-rich lipoprotein triglycerides. These persons also showed a higher apolipoprotein A1/apolipoprotein B ratio. Major allele homozygotes for i48168 and i27943 showed additionally higher high-density lipoproteins and lower postprandial apolipoprotein B. CONCLUSION: Our work shows that major allele homozygotes for ABCA1 single nucleotide polymorphisms i27943 and i48168 have a lower postprandial response as compared to minor allele carriers. This finding may further characterize the role of ABCA1 in lipid metabolism.

A set of miRNAs predicts T2DM remission in patients with coronary heart disease: from the CORDIOPREV study.

MicroRNAs (miRNAs) regulate the expression of genes associated with the development of diseases, including type 2 diabetes mellitus (T2DM). However, the use of miRNAs to predict T2DM remission has been poorly studied. Therefore, we aimed to investigate whether circulating miRNAs could be used to predict the probability of T2DM remission in patients with coronary heart disease. We included the newly diagnosed T2DM (n = 190) of the 1,002 patients from the CORDIOPREV study. Seventy-three patients reverted from T2DM after 5 years of dietary intervention with a low-fat or Mediterranean diet. Plasma levels of 56 miRNAs were measured by OpenArray. Generalized linear model, receiver operating characteristic (ROC), Cox regression, and pathway analyses were performed. ROC analysis based on clinical variables showed an area under the curve (AUC) of 0.66. After a linear regression analysis, seven miRNAs were identified as the most important variables in the group's differentiation. The addition of these miRNAs to clinical variables showed an AUC of 0.79. Cox regression analysis using a T2DM remission score including miRNAs showed that high-score patients have a higher probability of T2DM remission (hazard ratio [HR]low versus high, 4.44). Finally, 26 genes involved in 10 pathways were related to the miRNAs. We have identified miRNAs (hsa-let-7b, hsa-miR-101, hsa-miR-130b-3p, hsa-miR-27a, hsa-miR-30a-5p, hsa-miR-375, and hsa-miR-486) that contribute to the prediction of T2DM remission in patients with coronary heart disease.

Alcoholic and Non-Alcoholic Beer Modulate Plasma and Macrophage microRNAs Differently in a Pilot Intervention in Humans with Cardiovascular Risk.

Beer is a popular beverage and some beneficial effects have been attributed to its moderate consumption. We carried out a pilot study to test if beer and non-alcoholic beer consumption modify the levels of a panel of 53 cardiometabolic microRNAs in plasma and macrophages. Seven non-smoker men aged 30-65 with high cardiovascular risk were recruited for a non-randomised cross-over intervention consisting of the ingestion of 500 mL/day of beer or non-alcoholic beer for 14 days with a 7-day washout period between interventions. Plasma and urine isoxanthohumol were measured to assess compliance with interventions. Monocytes were isolated and differentiated into macrophages, and plasma and macrophage microRNAs were analysed by quantitative real-time PCR. Anthropometric, biochemistry and dietary parameters were also measured. We found an increase in plasma miR-155-5p, miR-328-3p, and miR-92a-3p after beer and a decrease after non-alcoholic beer consumption. Plasma miR-320a-3p levels decreased with both beers. Circulating miR-320a-3p levels correlated with LDL-cholesterol. We found that miR-17-5p, miR-20a-5p, miR-145-5p, miR-26b-5p, and miR-223-3p macrophage levels increased after beer and decreased after non-alcoholic beer consumption. Functional analyses suggested that modulated microRNAs were involved in catabolism, nutrient sensing, Toll-like receptors signalling and inflammation. We concluded that beer and non-alcoholic beer intake modulated differentially plasma and macrophage microRNAs. Specifically, microRNAs related to inflammation increased after beer consumption and decreased after non-alcoholic beer consumption.

Contribution of macronutrients to obesity: implications for precision nutrition.

The specific metabolic contribution of consuming different energy-yielding macronutrients (namely, carbohydrates, protein and lipids) to obesity is a matter of active debate. In this Review, we summarize the current research concerning associations between the intake of different macronutrients and weight gain and adiposity. We discuss insights into possible differential mechanistic pathways where macronutrients might act on either appetite or adipogenesis to cause weight gain. We also explore the role of dietary macronutrient distribution on thermogenesis or energy expenditure for weight loss and maintenance. On the basis of the data discussed, we describe a novel way to manage excessive body weight; namely, prescribing personalized diets with different macronutrient compositions according to the individual's genotype and/or enterotype. In this context, the interplay of macronutrient consumption with obesity incidence involves mechanisms that affect appetite, thermogenesis and metabolism, and the outcomes of these mechanisms are altered by an individual's genotype and microbiota. Indeed, the interactions of the genetic make-up and/or microbiota features of a person with specific macronutrient intakes or dietary pattern consumption help to explain individualized responses to macronutrients and food patterns, which might represent key factors for comprehensive precision nutrition recommendations and personalized obesity management.

Association Between Body Size Phenotypes and Subclinical Atherosclerosis.

CONTEXT: The underlying relationship between body mass index (BMI), cardiometabolic disorders, and subclinical atherosclerosis is poorly understood. OBJECTIVE: To evaluate the association between body size phenotypes and subclinical atherosclerosis. DESIGN: Cross-sectional. SETTING: Cardiovascular disease-free cohort. PARTICIPANTS: Middle-aged asymptomatic subjects (n = 3909). A total of 6 cardiometabolic body size phenotypes were defined based on the presence of at least 1 cardiometabolic abnormality (blood pressure, fasting blood glucose, triglycerides, low high-density lipoprotein cholesterol, homeostasis model assessment-insulin resistance index, high-sensitivity C-reactive protein) and based on BMI: normal-weight (NW; BMI <25), overweight (OW; BMI = 25.0-29.9) or obese (OB; BMI >30.0). MAIN OUTCOME MEASURES: Subclinical atherosclerosis was evaluated by 2D vascular ultrasonography and noncontrast cardiac computed tomography. RESULTS: For metabolically healthy subjects, the presence of subclinical atherosclerosis increased across BMI categories (49.6%, 58.0%, and 67.7% for NW, OW, and OB, respectively), whereas fewer differences were observed for metabolically unhealthy subjects (61.1%, 69.7%, and 70.5%, respectively). When BMI and cardiometabolic abnormalities were assessed separately, the association of body size phenotypes with the extent of subclinical atherosclerosis was mostly driven by the coexistence of cardiometabolic risk factors: adjusted OR = 1.04 (95% confidence interval [CI], 0.90-1.19) for OW and OR = 1.07 (95% CI, 0.88-1.30) for OB in comparison with NW, whereas there was an increasing association between the extent of subclinical atherosclerosis and the number of cardiometabolic abnormalities: adjusted OR = 1.21 (95% CI, 1.05-1.40), 1.60 (95% CI, 1.33-1.93), 1.92 (95% CI, 1.48-2.50), and 2.27 (95% CI, 1.67-3.09) for 1, 2, 3, and >3, respectively, in comparison with noncardiometabolic abnormalities. CONCLUSIONS: The prevalence of subclinical atherosclerosis varies across body size phenotypes. Pharmacologic and lifestyle interventions might modify their cardiovascular risk by facilitating the transition from one phenotype to another.

Postprandial Lipemia Modulates Pancreatic Alpha-Cell Function in the Prediction of Type 2 Diabetes Development: The CORDIOPREV Study.

Diabetes (T2DM) is a major global health issue, and developing new approaches to its prevention is of paramount importance. We hypothesized that abnormalities in lipid metabolism are involved in alpha-cell deregulation. We therefore studied the metabolic factors underlying alpha-cell dysfunction in T2DM progression after a dietary intervention (Mediterranean and low-fat). Additionally, we evaluated whether postprandial glucagon levels may be considered as a predictive factor of T2DM in cardiovascular patients. Non-T2DM participants from the CORDIOPREV study were categorized by tertiles of the area under the curve (AUC) for triacylglycerols and also by tertiles of AUC for glucagon. Our results showed that patients with higher triacylglycerols levels presented elevated postprandial glucagon (P = 0.009). Moreover, we observed higher risk of T2DM (hazard ratio: 2.65; 95% confidence interval: 1.56-4.53) in subjects with elevated glucagon. In conclusion, high postprandial lipemia may induce alpha-cell dysfunction in cardiovascular patients. Our results also showed that postprandial glucagon levels could be used to predict T2DM development.

Machine Learning Improves Cardiovascular Risk Definition for Young, Asymptomatic Individuals.

BACKGROUND: Clinical practice guidelines recommend assessment of subclinical atherosclerosis using imaging techniques in individuals with intermediate atherosclerotic cardiovascular risk according to standard risk prediction tools. OBJECTIVES: The purpose of this study was to develop a machine-learning model based on routine, quantitative, and easily measured variables to predict the presence and extent of subclinical atherosclerosis (SA) in young, asymptomatic individuals. The risk of having SA estimated by this model could be used to refine risk estimation and optimize the use of imaging for risk assessment. METHODS: The Elastic Net (EN) model was built to predict SA extent, defined by a combined metric of the coronary artery calcification score and 2-dimensional vascular ultrasound. The performance of the model for the prediction of SA extension and progression was compared with traditional risk scores of cardiovascular disease (CVD). An external independent cohort was used for validation. RESULTS: EN-PESA (Progression of Early Subclinical Atherosclerosis) yielded a c-statistic of 0.88 for the prediction of generalized subclinical atherosclerosis. Moreover, EN-PESA was found to be a predictor of 3-year progression independent of the baseline extension of SA. EN-PESA assigned an intermediate to high cardiovascular risk to 40.1% (n = 1,411) of the PESA individuals, a significantly larger number than atherosclerotic CVD (n = 267) and SCORE (Systematic Coronary Risk Evaluation) (n = 507) risk scores. In total, 86.8% of the individuals with an increased risk based on EN-PESA presented signs of SA at baseline or a significant progression of SA over 3 years. CONCLUSIONS: The EN-PESA model uses age, systolic blood pressure, and 10 commonly used blood/urine tests and dietary intake values to identify young, asymptomatic individuals with an increased risk of CVD based on their extension and progression of SA. These individuals are likely to benefit from imaging tests or pharmacological treatment. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians - The MUGELLO Study.

A total of 356 elderly subjects [257F; 88-106 years] were genotyped for three polymorphisms of the CLOCK gene by TaqMan real-time PCR approach, in order to find associations with quality of aging. Subjects homozygous for the minor allele of rs1801260 were less frequently overweight (p = 0.046), had higher fasting glucose levels (p = 0.037), better scores at the Clock Drawing Test (CDT) (p = 0.047) and worse scores at the Geriatric Depression Scale (p = 0.032). Subjects homozygous for the minor allele of rs11932595 showed higher fasting glucose levels (p = 0.044) and better scores at CDT (p = 0.030). Conversely, subjects homozygous for the minor allele of rs4580704 showed higher triglyceride (p = 0.012), and LDL-cholesterol levels (p = 0.44), and a greater adherence to the Mediterranean diet (MD) (p = 0.044). In addition, AAC, AAG, GGC and AGC (rs1801260-rs11932595-rs4580704) haplotypes were analyzed: AAG was associated with higher risk of overweight (p = 0.008), hypertriglyceridemia (p = 0.040) and hypercholesterolemia (p = 0.036); GGC with lower risk of hyperglycemia (p = 0.022), better sleep pattern (p = 0.001) and with better score at mini-mental state examination (p = 0.010); AGC with lower risk of depression (p = 0.026) and AAC with lower adherence to the MD (p = 0.028). Therefore, CLOCK gene polymorphisms let us hypothesize an involvement in the quality of aging in a cohort of nonagenarians.

Low Intake of Vitamin E Accelerates Cellular Aging in Patients With Established Cardiovascular Disease: The CORDIOPREV Study.

Leukocyte telomere length (LTL) shortening is a biomarker of cellular aging that can be decelerated by diet. We aimed to investigate the effect of dietary intake of vitamin E on biomarkers of cellular senescence in patients with established cardiovascular disease. To this end, DNA from 1,002 participants of the CORDIOPREV study (NCT00924937) was isolated and LTL was measured by real-time PCR. Dietary information was collected using a 146-item food frequency questionnaire, and several oxidative stress and damage biomarkers were determined. We found that patients with an inadequate intake of vitamin E according to the European Food Safety Authority, U.S. Food and Nutrition Board, and Spanish dietary recommendation had shorter LTL than those with an adequate intake (p = .004, p = .015, and p = .005, respectively). Moreover, we observed a positive correlation between olive oil, fish consumption and LTL (r2 = .083, p = .010; r2 = .090, p = .006, respectively). Subjects who consumed more than 30 mL olive oil/day had longer LTL than subjects with lower consumption (p = .013). Furthermore, we observed higher glutathione peroxidase activity in subjects consuming less vitamin E (p = .031). Our findings support the importance of an adequate consumption of the antioxidant vitamin E, and the value of the diet as a modulating tool of the senescence process.

Adiponectin gene variants are associated with insulin sensitivity in response to dietary fat consumption in Caucasian men.

Adiponectin (adipoQ) gene variants have been associated with type 2 diabetes mellitus and insulin resistance. Our aim was to examine whether the presence of several polymorphisms at the adipoQ gene locus (-11391 G > A, -11377 C > G, 45 T > G, and 276 G > T) influences the insulin sensitivity to dietary fat. Healthy volunteers (30 men and 29 women) consumed 3 diets for 4 wk each: an initial period during which all subjects consumed a SFA-rich diet (38% total fat, 20% SFA), followed by a carbohydrate-rich diet (CHO) (30% total fat, 55% carbohydrate) or a monounsaturated fatty acid (MUFA)-rich diet (38% total fat, 22% MUFA) following a randomized, crossover design. After participants consumed each diet, we tested peripheral insulin sensitivity with the insulin suppression test and measured plasma adiponectin concentrations. C/C homozygous men for the -11377 C > G single nucleotide polymorphism (SNP) had a significantly greater decrease in the steady-state plasma glucose concentrations when changing from the SFA-rich (8.95 +/- 0.6 mmol/L) to the MUFA-rich (6.04 +/- 0.31 mmol/L) and CHO-rich (6.35 +/- 0.38 mmol/L) diets than did those carrying the minor G allele (SFA, 6.65 +/- 0.4 mmol/L; MUFA, 6.45 +/- 0.4 mmol/L; CHO, 5.83 +/- 0.3 mmol/L) (P sex x gene x diet interaction = 0.016). These differences did not occur in female participants. Furthermore, C/C men had lower plasma adiponectin concentrations than did C/C women (P sex x gene interaction = 0.015), independently of the dietary fat consumed. None of the variables examined were significantly associated with -11426 A > G, 45T > G, or 276 G > T SNP. In conclusion, C/C homozygous men for the -11377 C > G SNP at adipoQ gene were significantly less insulin resistant after consumption of the MUFA- and CHO-rich diets compared with the SFA-rich diet. This information should help in the identification of vulnerable populations or persons who will benefit from more personalized and mechanism-based dietary recommendations.

[The role of omics in precision nutrition: strengths and weaknesses]. / Papel de las ómicas en la nutrición de precisión: fortalezas y debilidades.

Precision medicine has taken huge strides forward in recent years. Although there is still no generally accepted single definition, it basically considers the particular characteristics of each person as relevant in order to better adapt therapeutic or preventive measures in a more personalized fashion. Likewise, the concept of precision nutrition has gathered strength, in which the aim is to provide the best dietary recommendations to prevent or treat a disease in accordance with the characteristics of the individual in question. Of special importance among these characteristics are those based on omics. Initially genomics, and now epigenomics, metabolomics, proteomics and transcriptomics are providing us with new information on the different responses to the diet based on genotype, on new early biomarkers of disease, on dietary intake, or on the regulatory effects of diet. However, precision nutrition can go further still to include much more holistic aspects, not focusing on the disease, but on wellbeing and other indicators of positive health. Hence, other omics have been added to those mentioned above that provide us with a more multidimensional analysis. Gastronomy also plays an important role in precision nutrition. Although we are still at the preliminary validation stage of precision nutrition, this field presents huge potential for development. In this context, we shall review the role of omics in precision nutrition as well as their main strengths and weaknesses.

La medicina de precisión ha tomado un gran impulso en los últimos años. Aunque todavía no existe una definición única generalmente aceptada,se basa en considerar relevantes las características particulares de cada persona para adaptar mejor las medidas terapéuticas o preventivas de una manera más personalizada.De manera análoga, ha surgido el concepto de nutrición de precisión, en el que se pretende proporcionar las mejores recomendaciones dietéticas para prevenir o tratar una enfermedad de acuerdo con las características de la persona. Entre estas características cobran especial relevancia las basadas en las ómicas. Inicialmente, la genómica y, posteriormente, la epigenómica, la metabolómica, la proteómica y la transcriptómica están aportándonos nueva información sobre la distinta respuesta a la dieta basada en el genotipo, sobre nuevos biomarcadores precoces de enfermedad, sobre la ingesta o sobre efectos reguladores de la dieta. Pero la nutrición de precisión todavía puede extenderse mucho más incluyendo aspectos más holísticos que no estén centrados en la enfermedad, sino en el bienestar y otros indicadores de salud positiva. Para ello, a las mencionadas ómicas se han sumado otras ómicas que permiten un análisis más multidimensional.También la gastronomía tiene un papel relevante en la nutrición de precisión. Aunque todavía nos encontramos en una fase preliminar de estudio y de validación en nutrición de precisión, existe un gran potencial en este campo que es necesario desarrollar.En este contexto, revisaremos el papel de las ómicas en la nutrición de precisión, así como sus principales fortalezas y debilidades.

[Nutrigenetics, nutrigenomics and Mediterranean diet: a new vision for gastronomy]. / Nutrigenética, nutrigenómica y dieta mediterránea: una nueva visión para la gastronomía.

Both nutrigenetics and nutrigenomics are disciplines that form part of what is known as Nutritional Genomics, which, in the widest sense, provides the framework for integrating different omics with food and nutrition sciences. After decades of nutrigenetic and nutrigenomic studies, there is a large enough amount of knowledge to consider its application in so-called precision nutrition. This new discipline seeks to take into account the particular characteristics of the individual in order to provide the best diet for preventing or treating a disease. Omic markers are considered to be of importance to that personalization. There are many foods, nutrients and dietary patterns that have been researched in nutrigenetics and nutrigenomics, including the Mediterranean Diet pattern. Despite heterogeneity in defining the Mediterranean Diet, there are various studies that show that the Mediterranean Diet can interact with the genome, so reducing the risk of disease in the most genetically susceptible individuals. Likewise, several studies have recently been revealing the mechanisms through which the Mediterranean Diet may exercise this protective effect. Understanding genetic susceptibility, epigenetic mechanisms, the influence of the metabolome and other omics in more detail may be important in gastronomy, understood as the practice of selecting, cooking and eating food. This omic influence can not only be found in health-disease phenotypes, but also in food taste and smell perception and preferences for certain dishes. Considering all of these together may contribute to an increase in enjoying and at the same time pursuing healthy eating.

Tanto la nutrigenética como la nutrigenómica son disciplinas dentro de la denominada genómica nutricional, que, en sentido amplio, proporciona el marco de integración de las distintas ómicas con las ciencias de la alimentación y nutrición.Tras décadas de estudios nutrigenéticos y nutrigenómicos, se dispone de una cantidad relevante de conocimientos para plantear su aplicación en la denominada nutrición de precisión. Esta nueva disciplina plantea que hay que tener en cuenta las características particulares de la persona para proporcionar la mejor dieta para prevenir o tratar la enfermedad. Los marcadores ómicos se consideran relevantes en dicha personalización. Existen muchos alimentos, nutrientes y patrones de dieta que se han investigado en nutrigenética y nutrigenómica; entre ellos, podemos mencionar el patrón de dieta mediterránea.A pesar de la heterogeneidad en la definición de dieta mediterránea, existen varios estudios que muestran que la dieta mediterránea puede interaccionar con el genoma, disminuyendo el riesgo de enfermedad en las personas genéticamente más susceptibles. Paralelamente, algunos estudios están mostrando los mecanismos por los que la dieta mediterránea puede ejercer este efecto protector. Conocer con más detalle la susceptibilidad genética, los mecanismos epigenéticos, la influencia del metaboloma y de otras ómicas puede ser relevante en gastronomía, entendida como la práctica del arte de elegir, cocinar y comer los alimentos.Esta influencia ómica no solo podemos encontrarla en los fenotipos de salud-enfermedad, sino también en la percepción del sabor y del olor de los alimentos (las preferencias por determinadas comidas). Todo ello, bien integrado, puede contribuir al incremento del disfrute a la vez que se sigue una alimentación saludable.

A plasma circulating miRNAs profile predicts type 2 diabetes mellitus and prediabetes: from the CORDIOPREV study.

We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signaling and beta-cell function were measured by RT-PCR. We analyzed the relationship between miRNAs levels and insulin signaling and release indexes at baseline and after the follow-up period. The risk of developing disease based on tertiles (T1-T2-T3) of baseline miRNAs levels was evaluated by COX analysis. Thus, we observed higher miR-150 and miR-30a-5p and lower miR-15a and miR-375 baseline levels in subjects with T2DM than in disease-free subjects. Patients with high miR-150 and miR-30a-5p baseline levels had lower disposition index (p = 0.047 and p = 0.007, respectively). The higher risk of disease was associated with high levels (T3) of miR-150 and miR-30a-5p (HRT3-T1 = 4.218 and HRT3-T1 = 2.527, respectively) and low levels (T1) of miR-15a and miR-375 (HRT1-T3 = 3.269 and HRT1-T3 = 1.604, respectively). In conclusion, our study showed that deregulated plasma levels of miR-150, miR-30a-5p, miR-15a, and miR-375 were observed years before the onset of T2DM and pre-DM and could be used to evaluate the risk of developing the disease, which may improve prediction and prevention among individuals at high risk for T2DM.

Circulating miRNAs as Predictive Biomarkers of Type 2 Diabetes Mellitus Development in Coronary Heart Disease Patients from the CORDIOPREV Study.

Circulating microRNAs (miRNAs) have been proposed as type 2 diabetes biomarkers, and they may be a more sensitive way to predict development of the disease than the currently used tools. Our aim was to identify whether circulating miRNAs, added to clinical and biochemical markers, yielded better potential for predicting type 2 diabetes. The study included 462 non-diabetic patients at baseline in the CORDIOPREV study. After a median follow-up of 60 months, 107 of them developed type 2 diabetes. Plasma levels of 24 miRNAs were measured at baseline by qRT-PCR, and other strong biomarkers to predict diabetes were determined. The ROC analysis identified 9 miRNAs, which, added to HbA1c, have a greater predictive value in early diagnosis of type 2 diabetes (AUC = 0.8342) than HbA1c alone (AUC = 0.6950). The miRNA and HbA1c-based model did not improve when the FINDRISC was included (AUC = 0.8293). Cox regression analyses showed that patients with low miR-103, miR-28-3p, miR-29a, and miR-9 and high miR-30a-5p and miR-150 circulating levels have a higher risk of disease (HR = 11.27; 95% CI = 2.61-48.65). Our results suggest that circulating miRNAs could potentially be used as a new tool for predicting the development of type 2 diabetes in clinical practice.

Beneficial effect of CETP gene polymorphism in combination with a Mediterranean diet influencing lipid metabolism in metabolic syndrome patients: CORDIOPREV study.

The cholesteryl ester transfer protein (CETP) gene has been implicated in high-density lipoprotein (HDL-C) metabolism. However, little is known about the impact of this gene on metabolic syndrome (MetS) patients and its interaction with diet. Here, we evaluate whether the consumption of a Mediterranean diet, compared with a Low-fat diet, interacts with the rs3764261 SNP at the CETP locus to modify lipid metabolism in MetS patients. Plasma lipid concentrations and rs3764261 genotypes were determined in 424 MetS subjects participating in the CORDIOPREV clinical trial (NCT00924937). Gene-diet interactions were analyzed after a year of dietary intervention (Mediterranean diet (35% fat, 22% MUFA) vs Low-fat diet (28% fat, 12% MUFA)). We found significant gene-diet interactions between rs3764261 SNP and the dietary pattern for HDL-C (P = 0.006) and triglyceride concentrations (P = 0.040). Specifically, after 12 months of Mediterranean diet intervention, subjects who were carriers of the minor T allele (TT + TG) displayed higher plasma HDL-C concentrations (P = 0.021) and lower triglycerides (P = 0.020) compared with those who were homozygous for the major allele (GG). In contrast, in the Low-fat intervention group, no significant differences were found between CETP genotypes after 12 months of dietary treatment. Our data support the notion that the consumption of a Mediterranean diet may play a contributing role in triggering lipid metabolism by interacting with the rs3764261 SNP at CETP gene locus in MetS patients. Due to the complex nature of gene-environment interactions, dietary adjustment in MetS patients may require a personalized approach.

Postprandial lipemia is modified by the presence of the APOB-516C/T polymorphism in a healthy Caucasian population.

Apolipoprotein (apoB) plays a fundamental role in the transport and metabolism of plasma triacylglycerols (TAGs) and cholesterol. Several apoB polymorphic sites have been studied for their potential use as markers for coronary heart disease in the population. In view of the importance of apoB in postprandial metabolism, our objective was to determine whether the presence of the -516C/T polymorphism in the APOB gene promoter could influence postprandial lipoprotein metabolism in healthy subjects. Forty-seven volunteers who were homozygous for the E3 allele at the APOE gene were selected (30 homozygous for the common genotype (C/C) and 17 heterozygotes for the -516T allele (C/T). They were given a fat-rich meal containing 1 g fat and 7 mg cholesterol per kg body weight and vitamin A 60,000 IU/m(2) body surface. Fat accounted for 60% of calories, and protein and carbohydrates for 15 and 25% of energy, respectively. Blood samples were taken at time 0, every 1 h until 6 h, and every 2.5 h until 11 h. Total cholesterol and TAGs in plasma, and cholesterol, TAGs and retinyl palmitate in triacylglycerol-rich lipoproteins (large and small triacylglycerol-rich lipoproteins) were determined by ultracentrifugation. Individuals carrying the C/T genotype presented greater postprandial concentrations of TAGs in small triacylglycerol-rich lipoproteins than did carriers of the C/C genotype (P = 0.022). Moreover, C/T individuals presented higher concentrations of plasma TAGs during the postprandial period than did C/C subjects (P = 0.039). No other statistically significant genotype-related differences for other parameters were observed. These results suggest that the presence of the genotype C/T is associated with a higher postprandial response. Thus, the allele variability in the -516C/T polymorphism in the APOB gene promoter may partly explain the interindividual differences in postprandial lipemic response in healthy subjects.