Metabolites, genomics, epigenomics, exposomics and health: Focus on serum bilirubin concentrations in subjects with metabolic syndrome from a Mediterranean population

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)Although metabolomics aims at the measurement of small molecules (metabolites) in a biological sample, this knowledge requires additional information on the related genetic variants, epigenetic regulators and environmental factors (diet, smoking, physical activity, etc.) in order to translate the knowledge into actionable therapeutic or preventive evidence for complex disease outcomes. We focused on serum bilirubin, a metabolite generated when heme oxygenase catalyzes the degradation of heme (Figure 1). This produces biliverdin, which is converted into bilirubin by biliverdinreductase. Bilirubin is further processed in hepatocytes, where unconjugated bilirubin is conjugated by uridine diphosphate-glucuronosyltransferase (UDP-GT) to a water-soluble form for excretion. For decades, increased serum bilirubin concentrations were considered a threatening sign of underlying liver disease and had been associated with neonatal jaundice. However, data from recent years show that bilirubin is a powerful antioxidant and suggest that slightly increased serum bilirubin concentrations are protective against oxidative stress-related diseases

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

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

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

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

Influence of Demographic and Lifestyle Variables on Plasma Magnesium Concentrations and Their Associations with Cardiovascular Risk Factors in a Mediterranean Population

Several studies have shown that a low magnesium (Mg) intake in the diet is associated with greater cardiovascular risk and greater risk of diabetes. However, the results are not consistent in all populations. To minimize the biases derived from diet measurement, more objective biomarkers of magnesium status have been proposed. Although there is still no ideal biomarker for Mg, several studies have shown that plasma Mg concentrations could be a relatively acceptable biomarker for cardiovascular risk assessment. However, further studies are required to better characterize this marker in different populations. Our aim was to analyze the association between plasma Mg concentrations (measured through inductively coupled plasma mass spectrometry (ICP-MS)) methods, and cardiovascular risk factors in individuals from a general Mediterranean population (aged 18–80 years). The influence of demographic and lifestyle variables, including adherence to the Mediterranean diet, on plasma Mg concentrations was analyzed. The mean Mg level of the population studied was 0.77 ± 0.08 mmol/L, the prevalence of hypomagnesemia (<0.70 mmol/L) being 18.6%. We did not find any statistically significant differences between plasma Mg concentrations and sex, age, tobacco smoking and total adherence to the Mediterranean diet (p > 0.05). We found a statistically significant association between plasma Mg concentrations and the prevalence of type-2 diabetes (0.77 ± 0.08 mmol/L in non-diabetics versus 0.73 ± 0.13 mmol/L in diabetics; p = 0.009). Despite the low prevalence of type-2 diabetes in this population (11.24% in subjects with hypomagnesemia versus 3.91%, in normomagnesemia; p = 0.005), hypomagnesemia was associated with greater odds of being diabetic in comparison with normomagnesemia (OR = 3.36; p = 0.016, even after adjustment for sex, age, obesity, and medications). On the other hand, no statistically significant association of plasma Mg concentrations with obesity, hypertension, fasting triglycerides, HDL-cholesterol or uric acid was found. However, in contrast to what was initially expected, a statistically significant association was found between plasma Mg concentrations (basically in the highest quartile) and greater total cholesterol (p < 0.05) and LDL-cholesterol concentrations (p < 0.05). In conclusion, our results contribute to increasing the evidence gathered by numerous studies on the inverse association between hypomagnesemia and type-2 diabetes, as well as to the observation, previously reported in some studies, of a direct association with hypercholesterolemia. This paradoxical link should be deeply investigated in further studies.This study was partially funded, by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER) (grants CIBER 06/03, SAF2016–80532-R); the Junta de Andalucía (AGR145 research group); the University Jaume I (grant P1–1B2013–54); the Fundació La Marató de TV3 (grant 538/U/2016) and the Generalitat Valenciana (grants PROMETEO2017/017, and APOSTD/2019/136)

Influence of DNA-Polymorphisms in Selected Circadian Clock Genes on Clock Gene Expression in Subjects from the General Population and Their Association with Sleep Duration

Background and Objectives: Circadian rhythms have an important implication in numerous physiological and metabolic processes, including the sleep/wake cycle. Inter-individual differences in factors associated with circadian system may be due to gene differences in gene expression. Although several studies have analyzed the association between DNA polymorphisms and circadian variables, the influence on gene expression has been poorly analyzed. Our goal was to analyze the association of genetic variations in the clock genes and the gene expression level. Materials and Methods: We carried out a cross-sectional study of 102 adults (50.9% women). RNA and DNA were isolated from blood and single-nucleotide polymorphisms (SNPs), and the main circadian clock genes were determined. Gene expression of CLOCK, PER1, and VRK2 genes was measured by Reverse-transcription polymerase chain reaction (RT-PCR). The association between the DNA-SNPs and gene expression was analyzed at the gene level. In addition, a polygenic risk score (PRS), including all the significant SNPs related to gene expression, was created for each gene. Multivariable model analysis was performed. Results: Sex-specific differences were detected in PER1 expression, with these being higher in women (p = 0.034). No significant differences were detected in clock genes expression and lifestyle variables. We observed a significant association between the ARNTL-rs7924734, ARNTL-rs10832027, VRK2- rs2678902 SNPs, and CLOCK gene expression; the PER3-rs228642 and PER3-rs10127838 were related to PER1 expression, and the ARNTL-rs10832027, ARNTL-rs11022778, and MNTR1B-rs10830963 were associated with VRK2 gene expression (p < 0.05). The specific PRS created was significantly associated with each of the gene expressions analyzed (p < 0.001). Finally, sleep duration was associated with PER3-rs238666 (p = 0.008) and CLOCK-rs4580704 (p = 0.023). Conclusion: We detected significant associations between DNA-SNPs in the clock genes and their gene expression level in leukocytes and observed some differences in gene expression per sex. Moreover, we reported for the first time an association between clock gene polymorphisms and CLOCK, PER1, and VRK2 gene expression. These findings need further investigation