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

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

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

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

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

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

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

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

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