Relationship between blood DNA methylation, diet quality indices and metabolic health: Data from Obekit study Aline Rosignoli da Conceição, Josefina Bressan, Marta Cuervo, Maria Luisa Mansego, J. Alfredo Martínez, José Ignacio Riezu-Boj, Fermín I. Milagro Journal of Nutritional Biochemistry, 2025 • A total of 4 FDR-significant correlations were found between nutrients and CpGs. • A DMR in ZFP57 gene was closely related to obesity and dietary factors. • hPDI and UPF presented the most predictive models of diet quality based on DNAm. • hPDI and UPF were the best indices for predicting the main metabolic risk factors. • Specific nutrients and diet quality indices may influence the degree of DNAm. Epigenetic mechanisms, which can be modulated by dietary factors, have been proposed as a possible factor in understanding interindividual differences in disease susceptibility. We aimed to determine the relationships between DNA methylation (DNAm), diet quality, and metabolic health in Spanish individuals. This is a transversal study encompassing 337 male and female participants in the Obekit study. Diet quality was assessed using a validated semiquantitative food frequency questionnaire and seven previously established scores: overall, healthy and unhealthy Plant-Based Diet Index (PDI, hPDI and uPDI, respectively), dietary diversity score (DDS), unprocessed/minimally processed foods (MPF) and ultra-processed foods (UPF) consumption and Mediterranean diet (MD) score. DNAm was analyzed in white blood cells using the Infinium MethylationEPIC v1.0 BeadChip kit. After filtering by a variance >0.36, we have worked with 5,261 CpG sites. We found four false discovery rate (FDR)-significant correlations between nutrients and CpGs sites: cg00167275 ( GLUD1 ) correlated with alcohol, cg05218090 with folic acid, cg16682935 ( PAPSS2 ) with selenium, and cg09821790 ( SLC7A6 ) with fish food. One differentially methylated region (DMR) located at zinc finger protein gene 57 ( ZFP57 ) was closely related to obesity and specific nutrients, food groups, and diet quality indices. The regression models of diet quality based on DNAm demonstrated that the most predictive values were when UPF and hPDI were considered. Also, UPF and hPDI were the best indices for predicting the main cardiometabolic risk factors. Our finding suggests that specific nutrients and diet quality indices may influence the degree of DNAm and putatively, the metabolic health in Spanish individuals.
Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration Ariadna Fernández-Calvet, Leticia Matilla-Cuenca, María Izco, Susanna Navarro, Miriam Serrano, Salvador Ventura, Javier Blesa, Maite Herráiz, Gorka Alkorta-Aranburu, Sergio Galera, Igor Ruiz de los Mozos, María Luisa Mansego, Alejandro Toledo-Arana, Lydia Alvarez-Erviti, Jaione Valle Nature Communications, 2024 Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson’s disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies.
MiR-1185-1 and miR-548q are biomarkers of response to weight loss and regulate the expression of GSK3B Marcos Garcia-Lacarte, Maria L. Mansego, M. Angeles Zulet, J. Alfredo Martinez, Fermin I. Milagro Cells, 2019 The aim of the present investigation was to identify putative miRNAs involved in the response to weight loss. Reverse-transcribed RNA isolated from white blood cells (WBCs) of a subpopulation from the Reduction of the Metabolic Syndrome in Navarra-Spain (RESMENA-S) study (low-responders (LR) and high-responders (HR)) was hybridized in a gene expression microarray. Moreover, miRNAs were sequenced by miRNA-Seq. It was found that miR-548q and miR-1185-1 were overexpressed in HR, both in the microarray and in the miRNA-Seq. A bioinformatic prediction of putative target genes of the selected miRNAs found that GSK3B, a putative target for miR-548q and miR-1185-1, was downregulated in HR. Particular 3′-UTR binding regions of GSK3B were cloned downstream of the firefly luciferase gene. HEK-293T cells were co-transfected with either 0.25 μg of empty pmiR-GLO or pmiR-GLO-548q-3′-UTR/pmiR-GLO-1185-1-3′-UTR, and 7.5 pmol of miR-548q/miR-1185-1 mimics, demonstrating that miR-1185-1 bound to the 3′-UTR region of GSK3B. THP-1 cells were transfected with either 20/40 nM of miR-548q/miR-1185-1 mimics, evidencing that miR-1185-1inhibited the expression of the gene when transfected at doses of 20/40 nM, whereas miR-548q inhibited GSK3B expression at a dose of 40 nM. As a conclusion, miR-548q and miR-1185-1 levels in WBCs are biomarkers of response to weight-loss diets and could be involved in the regulation of the proinflammatory gene GSK3B.
Epigenome-wide association study in peripheral white blood cells involving insulin resistance Ana Arpón, Fermín I. Milagro, Omar Ramos-Lopez, M. Luisa Mansego, José Luis Santos, José-Ignacio Riezu-Boj, J. Alfredo Martínez Scientific Reports, 2019 Insulin resistance (IR) is a hallmark of type 2 diabetes, metabolic syndrome and cardiometabolic risk. An epigenetic phenomena such as DNA methylation might be involved in the onset and development of systemic IR. The aim of this study was to explore the genetic DNA methylation levels in peripheral white blood cells with the objective of identifying epigenetic signatures associated with IR measured by the Homeostatic Model Assessment of IR (HOMA-IR) following an epigenome-wide association study approach. DNA methylation levels were assessed using Infinium Methylation Assay (Illumina), and were associated with HOMA-IR values of participants from the Methyl Epigenome Network Association (MENA) project, finding statistical associations for at least 798 CpGs. A stringent statistical analysis revealed that 478 of them showed a differential methylation pattern between individuals with HOMA-IR ≤ 3 and > 3. ROC curves of top four CpGs out of 478 allowed differentiating individuals between both groups (AUC≈0.88). This study demonstrated the association between DNA methylation in some specific CpGs and HOMA-IR values that will help to the understanding and in the development of new strategies for personalized approaches to predict and prevent IR-associated diseases.
Methylome-wide association study in peripheral white blood cells focusing on central obesity and inflammation Ana Arpón, Fermín I. Milagro, Omar Ramos-Lopez, Maria L. Mansego, José-Ignacio Riezu-Boj, J. Alfredo Martínez Genes, 2019 Epigenetic signatures such as DNA methylation may be associated with specific obesity traits in different tissues. The onset and development of some obesity-related complications are often linked to visceral fat accumulation. The aim of this study was to explore DNA methylation levels in peripheral white blood cells to identify epigenetic methylation marks associated with waist circumference (WC). DNA methylation levels were assessed using Infinium Human Methylation 450K and MethylationEPIC beadchip (Illumina) to search for putative associations with WC values of 473 participants from the Methyl Epigenome Network Association (MENA) project. Statistical analysis and Ingenuity Pathway Analysis (IPA) were employed for assessing the relationship between methylation and WC. A total of 669 CpGs were statistically associated with WC (FDR < 0.05, slope ≥ |0.1|). From these CpGs, 375 CpGs evidenced a differential methylation pattern between females with WC ≤ 88 and > 88 cm, and 95 CpGs between males with WC ≤ 102 and > 102 cm. These differentially methylated CpGs are located in genes related to inflammation and obesity according to IPA. Receiver operating characteristic (ROC) curves of the top four significant differentially methylated CpGs separated by sex discriminated individuals with presence or absence of abdominal fat. ROC curves of all the CpGs from females and one CpG from males were validated in an independent sample (n = 161). These methylation results add further insights about the relationships between obesity, adiposity-associated comorbidities, and DNA methylation where inflammation processes may be involved.
DNA methylation in genes of longevity-regulating pathways: Association with obesity and metabolic complications Francisca Salas-Pérez, Omar Ramos-Lopez, María L. Mansego, Fermín I. Milagro, José L. Santos, José I. Riezu-Boj, J. Alfredo Martínez Aging, 2019 Aging is the main risk factor for most chronic diseases. Epigenetic mechanisms, such as DNA methylation (DNAm) plays a pivotal role in the regulation of physiological responses that can vary along lifespan. The aim of this research was to analyze the association between leukocyte DNAm in genes involved in longevity and the occurrence of obesity and related metabolic alterations in an adult population. Subjects from the MENA cohort (n=474) were categorized according to age (<45 vs 45>) and the presence of metabolic alterations: increased waist circumference, hypercholesterolemia, insulin resistance, and metabolic syndrome. The methylation levels of 58 CpG sites located at genes involved in longevity-regulating pathways were strongly correlated (FDR-adjusted< 0.0001) with BMI. Fifteen of them were differentially methylated (p<0.05) between younger and older subjects that exhibited at least one metabolic alteration. Six of these CpG sites, located at MTOR (cg08862778), ULK1 (cg07199894), ADCY6 (cg11658986), IGF1R (cg01284192), CREB5 (cg11301281), and RELA (cg08128650), were common to the metabolic traits, and CREB5, RELA, and ULK1 were statistically associated with age. In summary, leukocyte DNAm levels of several CpG sites located at genes involved in longevity-regulating pathways were associated with obesity and metabolic syndrome traits, suggesting a role of DNAm in aging-related metabolic alterations.
Epigenetic analyses tools for nutrition research Maria L. Mansego, Fermín I. Milagro, J. Alfredo Martínez Principles of Nutrigenetics and Nutrigenomics Fundamentals of Individualized Nutrition, 2019
PTPRS and PER3 methylation levels are associated with childhood obesity: results from a genome-wide methylation analysis M. Samblas, F. I. Milagro, M. L. Mansego, A. Marti, J. A. Martinez, and Pediatric Obesity, 2018 SummaryBackgroundThe global prevalence of childhood overweight and obesity has increased in the last years. Epigenetic dysregulation affecting gene expression could be a determinant in early‐life obesity onset and accompanying complications.ObjectiveThe aim of the present investigation was to analyse the putative association between DNA methylation and childhood obesity.MethodsDNA was isolated from white blood cells of 24 children obtained from the GENOI study and was hybridized in a 450K methylation array. Two CpG sites associated with obesity were validated in 91 children by MassArray® EpiTyper™ technology.ResultsGenome‐wide analysis identified 734 CpGs (783 genes) differentially methylated between cases (n = 12) and controls (n = 12). Ingenuity Pathway Analysis showed that these genes were involved in oxidative stress and circadian rhythm signalling pathways. Moreover, the DNA methylation levels of VIPR2, GRIN2D, ADCYAP1R1, PER3 and PTPRS regions correlated with the obesity trait. EpiTyper™ validation also identified significant correlations between methylation levels of CpG sites on PTPRS and PER3 with BMI z‐score.ConclusionsThis study identified several CpG sites and specifically several CpGs in the PTPRS and PER3 genes differentially methylated between obese and non‐obese children, suggesting a role for DNA methylation concerning development of childhood obesity.
Genomic and metabolomic profile associated to microalbuminuria Vannina G. Marrachelli, Daniel Monleon, Pilar Rentero, María L. Mansego, Jose Manuel Morales, Inma Galan, Remedios Segura, Fernando Martinez, Juan Carlos Martin-Escudero, Laisa Briongos, Pablo Marin, Gloria Lliso, Felipe Javier Chaves, Josep Redon Plos One, 2014
Arylesterase activity is associated with antioxidant intake and Paraoxonase-1 (PON1) gene methylation in metabolic syndrome patients following an energy restricted diet Excli Journal, 2014
Impact of obesity-related genes in Spanish population Fernando Martínez-García, María L Mansego, Gemma Rojo-Martínez, Griselda De Marco-Solar, Sonsoles Morcillo, Federico Soriguer, Josep Redón, Monica Pineda Alonso, Juan C Martín-Escudero, Richard S Cooper, Felipe J Chaves BMC Genetics, 2013
Different impacts of cardiovascular risk factors on oxidative stress Maria L. Mansego, Josep Redon, Sergio Martinez-Hervas, Jose T. Real, Fernando Martinez, Sebastian Blesa, Veronica Gonzalez-Albert, Guillermo T. Saez, Rafael Carmena, Felipe J. Chaves International Journal of Molecular Sciences, 2011
