Advances in Understanding the Molecular Basis of the Mediterranean Diet Effect

Posted with permission from the Annual Review of Food Science and Technology, Volume 9 by Annual Reviews, http://www.annualreviews.org.Increasingly, studies showing the protective effects of the Mediterranean diet (MedDiet) on different diseases (cardiovascular, diabetes, some cancers, and even total mortality and aging indicators) are being published. The scientific evidence level for each outcome is variable, and new studies are needed to better understand the molecular mechanisms whereby the MedDiet may exercise its effects. Here, we present recent advances in understanding the molecular basis of MedDiet effects, mainly focusing on cardiovascular diseases but also discussing other related diseases. There is heterogeneity in defining the MedDiet, and it can, owing to its complexity, be considered as an exposome with thousands of nutrients and phytochemicals. We review MedDiet composition and assessment as well as the latest advances in the genomic, epigenomic (DNA methylation, histone modifications, microRNAs, and other emerging regulators), transcriptomic (selected genes and whole transcriptome), and metabolomic and metagenomic aspects of the MedDiet effects (as a whole and for its most typical food components). We also present a critical review of the limitations of the studies undertaken and propose new analyses and greater bioinformatic integration to better understand the most important molecular mechanisms whereby the MedDiet as a whole, or its main food components, may exercise their protective effects

Genética y epigenética de la obesidad

Although obesity is the result of the interaction between genetic predisposition and environmental factors, we still have very little knowledge about their contribution. In recent years, genome-wide association studies (GWAs) have allowed us to identify many genes associated with common obesity, among them the following: FTO, MC4R, KCTD15, MTCH2, NEGR1, BDNF, FAIM2, TMEM18, etc. Moreover, several gene-environment interaction studies, have allowed us to know that the influence of genetic variants in these genes is not deterministic but is modulated by environmental factors among which diet and physical activity are the most relevant. In parallel, epigenetics has also developed, based on modifications and regulations that do not involve changes in the DNA sequence. Among the epigenetic regulators, the most important are methylation and microRNAs. Studies of genome-wide methylation have also allowed us to identify differentially methylated genes associated with obesity. In this review we will analyze the main genetic and epigenetic factors associated with obesity as well as its environmental modulation.Aunque la obesidad es el resultado de la interacción entre la predisposición genética y los factores ambientales, todavía tenemos un conocimiento muy escaso sobre su contribución. En los últimos años, los estudios de asociación de genoma completo, conocidos como GWAs, nos han permitido identificar muchos genes asociados con la obesidad común, entre ellos destacan los siguientes: FTO, MC4R, KCTD15, MTCH2, NEGR1, BDNF, FAIM2, TMEM18, etc. Varios estudios de interacción gen-ambiente, nos han permitido conocer que la influencia de las variantes genéticas en esto genes no es determinista sino que está modulada por factores ambientales entre los que destaca la dieta y la actividad física. Paralelamente, se ha desarrollado también la epigenética, basada en modificaciones y regulaciones en el ADN que no implican cambios de secuencia. Entre los reguladores epigenéticos, los más importantes son la metilación y los microRNAs. Los estudios de metilación de genoma completo nos han permitido también identificar genes diferencialmente metilados asociados con obesidad. En esta revisión analizaremos los principales factores genéticos y epigenéticos relevantes en obesidad así como su modulación ambiental

MicroRNAs and drinking: association between the Pre-miR-27a rs895819 polymorphism and alcohol consumption in a Mediterranean population

Recently, microRNAs (miRNA) have been proposed as regulators in the different processes involved in alcohol intake, and differences have been found in the miRNA expression profile in alcoholics. However, no study has focused on analyzing polymorphisms in genes encoding miRNAs and daily alcohol consumption at the population level. Our aim was to investigate the association between a functional polymorphism in the pre-miR-27a (rs895819 A>G) gene and alcohol consumption in an elderly population. We undertook a cross-sectional study of PREvención con DIeta MEDiterránea (PREDIMED)-Valencia participants (n = 1007, including men and women aged 67 ± 7 years) and measured their alcohol consumption (total and alcoholic beverages) through a validated questionnaire. We found a strong association between the pre-miR-27a polymorphism and total alcohol intake, this being higher in GG subjects (5.2 ± 0.4 in AA, 5.9 ± 0.5 in AG and 9.1 ± 1.8 g/day in GG; padjusted = 0.019). We also found a statistically-significant association of the pre-miR-27a polymorphism with the risk of having a high alcohol intake (>2 drinks/day in men and >1 in women): 5.9% in AA versus 17.5% in GG; padjusted < 0.001. In the sensitivity analysis, this association was homogeneous for sex, obesity and Mediterranean diet adherence. In conclusion, we report for the first time a significant association between a miRNA polymorphism (rs895819) and daily alcohol consumption

APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts

BackgroundApolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD), and the ε4 allele (APOE4) may interact with lifestyle factors that relate to brain structural changes, underlying the increased risk of AD. However, the exact role of APOE4 in mediating interactions between the peripheral circulatory system and the central nervous system, and how it may link to brain and cognitive aging requires further elucidation. In this analysis, we investigated the association between APOE4 carrier status and multimodal biomarkers (diet, blood markers, clinical diagnosis, brain structure, and cognition) in the context of gene–environment interactions.MethodsParticipants were older adults from a longitudinal observational study, the Boston Puerto Rican Health Study (BPRHS), who self-identified as of Puerto Rican descent. Demographics, APOE genotype, diet, blood, and clinical data were collected at baseline and at approximately 12th year, with the addition of multimodal brain magnetic resonance imaging (MRI) (T1-weighted and diffusion) and cognitive testing acquired at 12-year. Measures were compared between APOE4 carriers and non-carriers, and associations between multimodal variables were examined using correlation and multivariate network analyses within each group.ResultsA total of 156 BPRHS participants (mean age at imaging = 68 years, 77% female, mean follow-up 12.7 years) with complete multimodal data were included in the current analysis. APOE4 carriers (n = 43) showed reduced medial temporal lobe (MTL) white matter (WM) microstructural integrity and lower mini-mental state examination (MMSE) score than non-carriers (n = 113). This pattern was consistent with an independent sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) of n = 283 non-Hispanic White adults without dementia (mean age = 75, 40% female). Within BPRHS, carriers showed distinct connectivity patterns between multimodal biomarkers, characterized by stronger direct network connections between baseline diet/blood markers with 12-year blood/clinical measures, and between blood markers (especially lipids and cytokines) and WM. Cardiovascular burden (i.e., hypertension and diabetes status) was associated with WM integrity for both carriers and non-carriers.ConclusionAPOE4 carrier status affects interactions between dietary factors, multimodal blood biomarkers, and MTL WM integrity across ~12 years of follow-up, which may reflect increased peripheral-central systems crosstalk following blood–brain barrier breakdown in carriers

Education modulates the association of the FTO rs9939609 polymorphism with body mass index and obesity risk in the Mediterranean population

Objective To define whether the rs9939609 FTO (fat mass and obesity associated) single nucleotide polymorphism (SNP) is associated with anthropometric measurements and its modulation by educational level in a Mediterranean population. Methods We studied 3 independent adult samples: a random sample (n = 1580) from the general population (GP), obese hospital patients (OHP) (n = 203) and elderly subjects (n = 1027) with high cardiovascular risk (HCR). Weight and height were directly measured. Education and physical activity (PA) were measured using questionnaires. Results The rs9939609 presented heterogeneous associations with BMI. In the GP, the minor A-allele was significantly associated with greater BMI, following a co-dominant pattern (P = 0.009), whereas in the OHP this association was recessive (P = 0.004). Conversely, we did not find a significant association with BMI in the HCR group (P < 0.596). In the GP we found a significant interaction between the FTO SNP and education (P = 0.048). In the stratified analysis, no association of the FTO SNP with greater BMI in university subjects was detected (P = 0.786), whereas the association was observed in non-university subjects (P = 0.001). The FTO × education interaction (P = 0.020) was also observed in determining obesity risk in the GP. A-allele carriers had a greater risk of being obese only if they had no university education (OR: 1.56; 95%CI: 1.09–2.23 for TA and OR: 2.01; 95%CI: 1.27–3.26 for AA subjects). The interaction of the FTO with education remained significant even after adjustment for PA.This work was supported by grants from the Ministerio de Ciencia e Innovacio´n (CIBER CB06/03/0035, RD07/0067/ 0006, PI06-1326, PI07-0954, PI08-90002 and SAF-09- 12304), the Generalitat Valenciana (GVACOMP2010-181, BEST2010-211, BEST2010-032) and the National Heart, Lung, and Blood Institute grants HL-54776, National Institute of Diabetes and Digestive and Kidney Diseases, Grant Number DK075030 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research

Association of the rs4988235 in the lactase gene with obesity and its modulation by dairy products in a Mediterranean population

The -13910C>T polymorphism (rs4988235) upstream from the lactase (LCT) gene, strongly associated with lactase persistence (LP) in Europeans, is emerging as a new candidate for obesity. We aimed to analyze the association of this polymorphism with obesity-related variables and its modulation by dairy product intake in an elderly population. We studied 940 high-cardiovascular risk Spanish subjects (aged 67 ± 7 years). Dairy product consumption was assessed by a validated questionnaire. Anthropometric variables were directly measured, and metabolic syndrome-related variables were obtained. Prevalence of genotypes was: 38.0% CC (lactase nonpersistent (LNP)), 45.7% CT, and 16.3% TT. The CC genotype was not associated with lower milk or dairy product consumption in the whole population. Only in women was dairy intake significantly lower in CC subjects. The most important association was obtained with anthropometric measurements. CC individuals had lower weight (P = 0.032), lower BMI (29.7 ± 4.2 vs. 30.6 ± 4.2 kg/m(2); P = 0.003) and lower waist circumference (101.1 ± 11.8 vs. 103.5 ± 11.5 cm; P = 0.005) than T-allele carriers. Obesity risk was also significantly higher in T-allele carriers than in CC individuals (odds ratio (OR): 1.38; 95% confidence interval (CI): 1.05-1.81; P = 0.01), and remained significant even after adjustment for sex, age, diabetes, physical activity, and energy intake. However, in subgroup analysis, these associations were found to be significant only among those consuming moderate or high lactose intakes (>8 g/day). No significant associations with lipids, glucose, or blood pressure were obtained after adjustment for BMI. In conclusion, despite not finding marked differences in dairy product consumption, this polymorphism was strongly associated with BMI and obesity and modulated by lactose intake in this MediterraneanLactase, Obesity, Gene, Dairy products, Lactose, Metabolic syndrome, Mediterranean This work was supported by grants from the Ministerio de Ciencia e Innovación, Spain (CIBER CB06/03/0035, RD07/0067/0006, PI6-1326, PI07-0954, PI08-90002 and SAF-09-12304), the Generalitat Valenciana, Spain (GVACOMP2010-181, BEST2010-211, BEST2010-032) and the National Heart, Lung, and Blood Institute grants HL-54776, National Institute of Diabetes and Digestive and Kidney Diseases, Grant Number DK075030 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Researc

Nutrigenetics, nutrigenomics and Mediterranean diet: a new vision for gastronomy

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.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

Aragon workers’ health study – design and cohort description

BACKGROUND: Spain, a Mediterranean country with relatively low rates of coronary heart disease, has a high prevalence of traditional cardiovascular risk factors and is experiencing a severe epidemic of overweight/obesity. We designed the Aragon Workers’ Health Study (AWHS) to characterize the factors associated with metabolic abnormalities and subclinical atherosclerosis in a middle aged population in Spain free of clinical cardiovascular disease. The objective of this paper is to describe the study design, aims and baseline characteristics of participants in the AWHS. METHODS/DESIGN: Longitudinal cohort study based on the annual health exams of 5,400 workers of a car assembly plant in Figueruelas (Zaragoza, Spain). Study participants were recruited during a standardized clinical exam in 2009–2010 (participation rate 95.6%). Study participants will undergo annual clinical exams and laboratory assays, and baseline and triennial collection of biological materials for biobanking and cardiovascular imaging exams (carotid, femoral and abdominal ultrasonography, coronary calcium score, and ankle-arm blood pressure index). Participants will be followed-up for 10 years. RESULTS: The average (SD) age, body mass index, and waist circumference were 49.3 (8.7) years, 27.7 (3.6) kg/m(2) and 97.2 (9.9) cm, respectively, among males (N = 5,048), and 40.8 (11.6) years, 24.4 (3.8) kg/m(2), and 81.9 (9.9) cm, among females (N = 351). The prevalence of overweight, obesity, current smoking, hypertension, hypercholesterolemia, and diabetes were 55.0, 23.1, 37.1, 40.3, 75.0, and 7.4%, respectively, among males, and 23.7, 8.3, 45.0, 12.1, 59.5, and 0.6%, respectively, among females. In the initial 587 study participants who completed all imaging exams (94.5% male), the prevalence of carotid plaque, femoral plaque, coronary calcium score >1 to 100, and coronary calcium score >100 was 30.3, 56.9, 27.0, and 8.8%, respectively. 67.7% of study participants had at least one plaque in the carotid or femoral arteries. DISCUSSION: Baseline data from the AWHS show a high prevalence of cardiovascular risk factors and of sublinical atherosclerosis. Follow-up of this cohort will allow the assessment of subclinical atherosclerosis progression and the link of disease progression to traditional and emergent risk factors

Candidate Gene and Genome-Wide Association Studies for Circulating Leptin Levels Reveal Population and Sex-Specific Associations in High Cardiovascular Risk Mediterranean Subjects

Leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its plasma levels are still not well known. Results of studies investigating polymorphisms in candidate genes have been inconsistent, and, in addition, very few genome-wide association studies (GWAS) have been undertaken. Our aim was to investigate the genes and gene variants most associated with plasma leptin concentrations in a high-cardiovascular-risk Mediterranean population. We measured plasma leptin in 1011 men and women, and analyzed the genetic factors associated using three approaches: (1) Analyzing the single nucleotide polymorphisms (SNPs) reported in a GWAS meta-analysis in other populations (including an SNP in/near each of these LEP, SLC32A1, GCKR, CCNL, COBLL1, and FTO genes); (2) Investigating additional SNPs in/near those genes, also including the RLEP gene; and (3) Undertaking a GWAS to discover new genes. We did not find any statistically significant associations between the previously published SNPs and plasma leptin (Ln) in the whole population adjusting for sex and age. However, on undertaking an extensive screening of other gene variants in those genes to capture a more complete set of SNPs, we found more associations. Outstanding among the findings was the heterogeneity per sex. We detected several statistically significant interaction terms with sex for these SNPs in the candidate genes. The gene most associated with plasma leptin levels was the FTO gene in men (specifically the rs1075440 SNP) and the LEPR in women (specifically the rs12145690 SNP). In the GWAS on the whole population, we found several new associations at the p < 1 × 10-5 level, among them with the rs245908-CHN2 SNP (p = 1.6 × 10-6). We also detected a SNP*sex interaction at the GWAS significance level (p < 5 × 10-8), involving the SLIT3 gene, a gene regulated by estrogens. In conclusion, our study shows that the SNPs selected as relevant for plasma leptin levels in other populations, are not good markers for this Mediterranean population, so supporting those studies claiming a bias when generalizing GWAS results to different populations. These population-specific differences may include not only genetic characteristics, but also age, health status, and the influence of other environmental variables. In addition, we have detected several sex-specific effects. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations