Interacción genético-ambiental en la modulación de adipocitoquinas y marcadores de inflamación en su asociación con obesidad y otros factores de riesgo cardiovascular en población mediterránea

La obesidad es una enfermedad metabólica resultado del desequilibrio entre el consumo y el gasto energético, con el consecuente aumento de la cantidad de grasa corporal. Este aumento de grasa corporal produce un desequilibrio en la secreción de adipocitoquinas y marcadores de inflamación relacionado con diversas complicaciones clínicas asociadas con la obesidad y otros factores de riesgo cardiovascular. Las investigaciones de las últimas décadas han permitido un notable aumento en la compresión de los mecanismos moleculares que regulan la homeostasis de la energía, poniendo de manifiesto la importancia de los factores ambientales en la modulación de las reservas energéticas. Además, la variabilidad individual en la respuesta a estos factores ambientales refleja la influencia de la carga genética en la regulación de la energía, demostrando la existencia de una relación sinérgica entre los genes, la conducta y el medio ambiente en el desarrollo de la obesidad. De ahí estriba la importancia del estudio de las interacciones gen*ambiente en el desarrollo de las enfermedades de origen multifactorial como es el caso de la obesidad. Entre los distintos factores ambientales en la prevención de la obesidad, tras décadas en las que las recomendaciones dietéticas estaban basadas en una dieta baja en grasa, en los últimos años la dieta mediterránea se esta imponiendo como alternativa más saludable. Actualmente en España se está llevando a cabo el estudio PREDIMED (Prevención con Dieta MEDiterránea); ensayo prospectivo, aleatorizado, multicéntrico y controlado de intervención para analizar los efectos de la dieta mediterránea en la prevención primaria de la enfermedad cardiovascular. Nuestro grupo investigador participa como el nodo de Valencia donde se han reclutado 1050 participantes con elevado riesgo cardiovascular constituyendo el tamaño muestral de esta tesis doctoral. Se realizó un estudio transversal del estudio PREDIMED de Valencia, centrándonos en los datos de la visita basal. Se analizó la concentración de adiponectina, leptina y ácidos grasos no esterificados (AGNE) y su modulación por factores ambientales (tabaco, actividad física y dieta), así como la influencia de polimorfismos en genes candidatos (ADIPOQ, ADIPOR1, LEP, RLEP, GHRL, GHSR, PYY, MC4R, CNR1, BDNF, NPY2R, KCNJ11, ABCC8, ENPP1, TSPAN8, CD36, MLXIPL, MCM6 y NR1H3) y su asociación con obesidad y otros factores de riesgo cardiovascular, como con parámetros relacionados (datos bioquímicos y antropométricos, presión arterial y marcadores de inflamación) y las variaciones fenotípicas expresadas en función de las interacciones gen*gen y gen*ambiente. Los resultados más relevantes han mostrado que, la concentración plasmática de adiponectina en esta población se relaciona con un perfil lipídico más favorable y una menor presencia de factores de riesgo cardiovascular. En cambio, las concentraciones de leptina y AGNE se muestran aumentadas en individuos con mayor peso y un perfil de riesgo cardiovascular más desfavorable. También algunas de las variantes genéticas estudiadas han mostrado importantes asociaciones significativas con los fenotipos de interés (niveles de adipocitoquinas y de AGNE, parámetros bioquímicos y antropométricos y presión arterial), además de una elevada relevancia en el riesgo de obesidad y otros factores de riesgo cardiovascular. Paralelamente, se han detectado interacciones gen*gen en la determinación de factores relacionados con la obesidad. Estas interacciones muestran que el impacto de una variante genética sobre un fenotipo también puede depender de la presencia de otra variante en otro gen distinto. Del mismo modo, hemos encontrado interacciones gen*ambiente, donde se observa que los efectos de determinadas variantes genéticas pueden ser modulados por distintos factores ambientales. Por lo que la detección de estas modulaciones constituye una evidencia de la importancia de la consideración tanto de factores genéticos como ambientales en el estudio de la obesidad y otros factores de riesgo cardiovascular.Obesity is a metabolic disease associated with several cardiovascular risk factors (CVRF). Environmental factors have a major impact on the obesity modulation, however, individual variability in response to these factors highlights the influence of genetic profile. That is the reason of the importance of the study of gene*environment interactions in determining obesity and other CVRF. We have carried out a cross-sectional study on participants in PREDIMED (PREvención DIeta MEDiterránea) trial who were recruited in the Valencia field center. This study is a randomized interventional trial, to assess the effects of the Mediterranean Diet on the primary prevention of cardiovascular disease. We included 1050 participants and baseline concentrations of adiponectin, leptin and non-esterificated fatty acids (NEFA) were analyzed. Moreover, the modulation of these parameters by environmental factors (smoking, physical activity and diet), and the influence of polymorphisms in candidates genes (ADIPOQ, ADIPOR1, LEP, RLEP, GHRL, GHSR, PYY, MC4R, CNR1, BDNF, NPY2R, KCNJ11, ABCC8, ENPP1, TSPAN8, CD36, MLXIPL, MCM6, and NR1H3) was analyzed. In addition, the associations and interactions between these polymorphisms and environmental factors in determining obesity and other CVRF including biochemical and anthropometric data and blood pressure were studied also focusing on gene*gene and gene*environment interactions. Our results have shown that the plasma concentration of adiponectin was associated with a lower cardiovascular risk profile. However, the increased leptin and NEFA concentrations were associated with a less favourable cardiovascular risk profile. Moreover, some of the genetic variants studied showed significant associations with concentrations of adiponectin, leptin and NEFA. In addition, other biochemical and anthropometric parameters and blood pressure were associated with the selected polymorphisms. We have detected some gene*gene interactions in the evaluation of obesity related factors. These interactions showed that the impact of a genetic variant on the selected phenotype may also depend on the presence of another variant in another different gene. Similarly, several gene*environment interactions were found, indicating that the effects of a particular genetic variants are modulated by environmental factors. So, the detection of these modulations is an evidence of the importance of considering both genetic and environmental factors in the study of obesity and other CVRF

Crosstalk between smoking and the genome in older subjects with metabolic syndrome through genomics, epigenomics and transcriptomics

Pòster presentat a EMBO - EMBL Symposia Multiomics to Mechanisms - Challenges in Data Integration. September (11th – 13th 2019 European Molecular Biology Laboratory. Heidelberg, Germany)Tobacco smoking (Figure 1) is a major cause of cardiovascular diseases (CVD), and appears to have a multiplicative interaction with the other major CVD risk factors (lipids, hypertension, diabetes and others present in the metabolic syndrome (MetS). Several omics have analyzed the separate effects of tobacco smoking on the genome, epigenome, transcriptome, metabolome, etc. However an integrated omics approach can help to better understand the crosstalk between tobacco smoking and the genome

Untargeted metabolomics based on ultra-high-performance liquid chromatography-ion mobility-quadrupole time-of-flight mass spectrometry for biomarker discovery of orange intake in a cross-over trial

Pòster presentat al congrés "Understanding Human Diseases Through Metabolomics: Interactions Among the Genome, Proteome, Gut Microbiome and Nutrition", Metabolomics and Human Health, Gordon Research Conference (February 3 - 8, 2019 Ventura, CA, United States)Diet is one of the most important lifestyle factors associated with health status. Currently, one of the main limitations of nutritional epidemiology and nutritional genomics is the difficulty in the measurements of dietary intake. In observational studies carried out in a large number of participants, the most commonly applied tools for estimating dietary intake are based on self-reporting, including food frequency questionnaires (FFQ) for the assessment of regular consumption (usually 1-year), or 24-h recalls for 1-day assessment. However, such instruments for data collection may contain several recall bias and other systematic or random errors that may have a great effect in the subsequent associations found. Although in recent years, it has been an improvement in increasing the validity and precision of food questionnaires due to the use of the new information technologies (Figure 1), these instruments are still biased and additional information based on objective biomarkers of food intake is needed

Ultra-Performance Liquid Chromatography-Ion Mobility Separation-Quadruple Time-of-Flight MS (UHPLC-IMS-QTOF MS) Metabolomics for Short-Term Biomarker Discovery of Orange Intake: A Randomized, Controlled Crossover Study

A major problem with dietary assessments is their subjective nature. Untargeted metabolomics and new technologies can shed light on this issue and provide a more complete picture of dietary intake by measuring the profile of metabolites in biological samples. Oranges are one of the most consumed fruits in the world, and therefore one of the most studied for their properties. The aim of this work was the application of untargeted metabolomics approach with the novel combination of ion mobility separation coupled to high resolution mass spectrometry (IMS-HRMS) and study the advantages that this technique can bring to the area of dietary biomarker discovery, with the specific case of biomarkers associated with orange consumption (Citrus reticulata) in plasma samples taken during an acute intervention study (consisting of a randomized, controlled crossover trial in healthy individuals). A total of six markers of acute orange consumption, including betonicines and conjugated flavonoids, were identified with the experimental data and previous literature, demonstrating the advantages of ion mobility in the identification of dietary biomarkers and the benefits that an additional structural descriptor, as the collision cross section value (CCS), can provide in this area

Circulating adiponectin and Its association with metabolic traits and Type 2 Diabetes: gene-diet interactions focusing on selected gene variants and at the genome-wide level in high-cardiovascular risk mediterranean subjects

Adiponectin is gaining renewed interest since, in addition to its possible protective role against insulin resistance and arteriosclerosis, recent studies suggest other additional favorable effects. However, the influence of gene-diet interactions on plasma adiponectin levels is still little understood. We analyzed the association between plasma adiponectin levels and various metabolic traits in a high-cardiovascular risk Mediterranean population, as well as the genetic effect of four candidate single-nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ) and their interactions with the Mediterranean dietary pattern. Additionally, we explored, at the genome-wide level, the SNPs most associated with plasma adiponectin levels, as well as gene–diet interactions with the Mediterranean diet. In the 954 participants studied (aged 55–80 years), plasma adiponectin levels were strongly associated with plasma HDL-C concentrations (p = 6.6 × 10−36) and inversely related to triglycerides (p = 4.7 × 10−18), fasting glucose (p = 3.5 × 10−16) and type 2 diabetes (p = 1.4 × 10−7). Of the four pre-selected ADIPOQ candidate SNPs, the one most associated with plasma adiponectin was the −11391G > A (rs17300539) promoter SNP (p = 7.2 × 10−5, in the multivariable adjusted model). No significant interactions with the Mediterranean diet pattern were observed for these SNPs. Additionally, in the exploratory genome-wide association study (GWAS), we found new SNPs associated with adiponectin concentrations at the suggestive genome-wide level (p < 1 × 10−5) for the whole population, including the lead SNP rs9738548 (intergenic) and rs11647294 in the VAT1L (Vesicle Amine Transport 1 Like) gene. We also found other promising SNPs on exploring different strata such as men, women, diabetics and non-diabetics (p = 3.5 × 10−8 for rs2850066). Similarly, we explored gene–Mediterranean diet interactions at the GWAS level and identified several SNPs with gene–diet interactions at p < 1 × 10−5. A remarkable gene–diet interaction was revealed for the rs2917570 SNP in the OPCML (Opioid Binding Protein/Cell Adhesion Molecule Like) gene, previously reported to be associated with adiponectin levels in some populations. Our results suggest that, in this high-cardiovascular risk Mediterranean population, and even though adiponectin is favorably associated with metabolic traits and lower type 2 diabetes, the gene variants more associated with adiponectin may be population-specific, and some suggestive gene–Mediterranean diet interactions were detected

Genome-wide association analyses of weight loss in a randomized controlled trial of lifestyle intervention, and combined transcriptome-wide associations in a Mediterranean population

Pòster presentat a EMBO - EMBL Symposia Multiomics to Mechanisms - Challenges in Data Integration. September (11th – 13th 2019 European Molecular Biology Laboratory. Heidelberg, Germany)Although large-scale genome-wide association studies (GWAS) for obesity traits have identified more than 400 associated loci from observational studies (Figure 1), we highlight the fact that currently the number of GWAS for intentional weight change in randomized controlled trials (RCT) of lifestyle interventions is very scarce. Only a few RCT on weight loss have been carried out and recently a GWAS including 2 populations (a Canadian RCT and the Diogenes RCT) was been published (Valsesia et al, Nat Communications, 2019). Likely, at the transcriptome level, there is a scarcity of transcriptome-wide association studies (TWAS) of weight loss in RCT. Moreover, this scarcity is higher for studies including subjects from the Mediterranean countries. Therefore, our first aim was to undertake a GWAS in overweight/obese subjects from a Mediterranean population (Spain) after 1-year lifestyle intervention (including an energy restricted Mediterranean diet plus physical activity) in a RCT to identify genetic variants associated with weight loss and related outcomes. In addition, as a second aim, we carried out a TWAS in a subsample of subjects for the same intervention to identify changes in gene expression and related pathways

The Gln241His polymorphism in the carbohydrate response element binding protein (MLXIPL) gene

Comunicació presentada com a pòster a European Association of Human Genetics Conference, May 23-26, 2009, Vien

Circulating Adiponectin and Its Association with Metabolic Traits and Type 2 Diabetes: Gene-Diet Interactions Focusing on Selected Gene Variants and at the Genome-Wide Level in High-Cardiovascular Risk Mediterranean Subjects

Adiponectin is gaining renewed interest since, in addition to its possible protective role against insulin resistance and arteriosclerosis, recent studies suggest other additional favorable effects. However, the influence of gene-diet interactions on plasma adiponectin levels is still little understood. We analyzed the association between plasma adiponectin levels and various metabolic traits in a high-cardiovascular risk Mediterranean population, as well as the genetic effect of four candidate single-nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ) and their interactions with the Mediterranean dietary pattern. Additionally, we explored, at the genome-wide level, the SNPs most associated with plasma adiponectin levels, as well as gene-diet interactions with the Mediterranean diet. In the 954 participants studied (aged 55-80 years), plasma adiponectin levels were strongly associated with plasma HDL-C concentrations (p = 6.6 × 10-36) and inversely related to triglycerides (p = 4.7 × 10-18), fasting glucose (p = 3.5 × 10-16) and type 2 diabetes (p = 1.4 × 10-7). Of the four pre-selected ADIPOQ candidate SNPs, the one most associated with plasma adiponectin was the -11391G > A (rs17300539) promoter SNP (p = 7.2 × 10-5, in the multivariable adjusted model). No significant interactions with the Mediterranean diet pattern were observed for these SNPs. Additionally, in the exploratory genome-wide association study (GWAS), we found new SNPs associated with adiponectin concentrations at the suggestive genome-wide level (p < 1 × 10-5) for the whole population, including the lead SNP rs9738548 (intergenic) and rs11647294 in the VAT1L (Vesicle Amine Transport 1 Like) gene. We also found other promising SNPs on exploring different strata such as men, women, diabetics and non-diabetics (p = 3.5 × 10-8 for rs2850066). Similarly, we explored gene-Mediterranean diet interactions at the GWAS level and identified several SNPs with gene-diet interactions at p < 1 × 10-5. A remarkable gene-diet interaction was revealed for the rs2917570 SNP in the OPCML (Opioid Binding Protein/Cell Adhesion Molecule Like) gene, previously reported to be associated with adiponectin levels in some populations. Our results suggest that, in this high-cardiovascular risk Mediterranean population, and even though adiponectin is favorably associated with metabolic traits and lower type 2 diabetes, the gene variants more associated with adiponectin may be population-specific, and some suggestive gene-Mediterranean diet interactions were detected

Influence of the adherence to the Mediterranean diet on the effect of smoking on genomewide methylation among subjects with metabolic syndrome

Pòster presentat al congrés " Epigenetics: Playing with the Gameof Life" celebrat al University Hospital Halle (Saale) entre els dies 13-15 de 2019.Tobacco smoking is an important risk factor for lung cancer, respiratory diseases and cardiovascular diseases, among others. Moreover, smoking can speed up the normal aging process of several tissues increasing the biological age. Changes in methylation due to smoking have been demonstrated at several loci across the genome, particularly in long-term smokers (Figure 1). The most consistent association reported in different populations has been decreased methylation in smokers in comparison with non-smokers at the CpG cg05575921, located in the gene for the aryl hydrocarbon receptor repressor (AHRR) located in chromosome 5

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