Ramos-López, O. (Omar)
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- Models integrating genetic and lifestyle interactions on two adiposity phenotypes for personalized prescription of energy-restricted diets with different macronutrient distribution(Frontiers Media SA, 2019) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Goñi-Mateos, L. (Leticia); Milagro-Yoldi, F.I. (Fermín Ignacio); Cuervo, M. (Marta); Ramos-López, O. (Omar)Aim: To analyze the influence of genetics and interactions with environmental factors on adiposity outcomes [waist circumference reduction (WCR) and total body fat loss (TFATL)] in response to energy-restricted diets in subjects with excessive body weight. Materials and Methods: Two hypocaloric diets (30% energy restriction) were prescribed to overweight/obese subjects during 16 weeks, which had different targeted macronutrient distribution: a low-fat (LF) diet (22% energy from lipids) and a moderately high-protein (MHP) diet (30% energy from proteins). At the end of the trial, a total of 201 participants (LF diet = 105; MHP diet = 96) who presented good/regular dietary adherence were genotyped for 95 single nucleotide polymorphisms (SNPs) previously associated with weight loss through next-generation sequencing from oral samples. Four unweighted (uGRS) and four weighted (wGRS) genetic risk scores were computed using statistically relevant SNPs for each outcome by diet. Predictions of WCR and TFATL by diet were modeled through recognized multiple linear regression models including genetic (single SNPs, uGRS, and wGRS), phenotypic (age, sex, and WC, or TFAT at baseline), and environment variables (physical activity level and energy intake at baselines) as well as eventual interactions between genes and environmental factors. Results: Overall, 26 different SNPs were associated with differential adiposity outcomes, 9 with WCR and 17 with TFATL, most of which were specific for each dietary intervention. In addition to conventional predictors (age, sex, lifestyle, and adiposity status at baseline), the calculated uGRS/wGRS and interactions with environmental factors were major contributors of adiposity responses. Thus, variances in TFATL-LF diet, TFATL-MHP diet, WCR-LF diet, and WCR-MHP diet were predicted by approximately 38% (optimism-corrected adj. R2 = 0.3792), 32% (optimism-corrected adj. R2 = 0.3208), 22% (optimism-corrected adj. R2 = 0.2208), and 21% (optimism-corrected adj. R2 = 0.2081), respectively. Conclusions: Different genetic variants and interactions with environmental factors modulate the differential individual responses to MHP and LF dietary interventions. These insights and models may help to optimize personalized nutritional strategies for modeling the prevention and management of excessive adiposity through precision nutrition approaches taking into account not only genetic information but also the lifestyle/clinical factors that interplay in addition to age and sex.
- Exploring host genetic polymorphisms involved in SARS-CoV infection autcomes: implications for personalized medicine in COVID-19(Hindawi, 2020) Martinez, J.A. (José Alfredo); Daimiel, L. (Lidia); Vargas, J.A. (Juan A.); Martinez-Urbistondo, D. (Diego); Ramirez-de-Molina, A. (Ana); Ramos-López, O. (Omar)Objective. To systematically explore genetic polymorphisms associated with the clinical outcomes in SARS-CoV infection in humans. Methods. This comprehensive literature search comprised available English papers published in PubMed/Medline and SCOPUS databases following the PRISMA-P guidelines and PICO/AXIS criteria. Results. Twenty-nine polymorphisms located in 21 genes were identified as associated with SARS-CoV susceptibility/resistance, disease severity, and clinical outcomes predominantly in Asian populations. Thus, genes implicated in key pathophysiological processes such as the mechanisms related to the entry of the virus into the cell and the antiviral immune/inflammatory responses were identified. Conclusions. Although caution must be taken, the results of this systematic review suggest that multiple genetic polymorphisms are associated with SARS-CoV infection features by affecting virus pathogenesis and host immune response, which could have important applications for the study and understanding of genetics in SARS-CoV-2/COVID-19 and for personalized translational clinical practice depending on the population studied and associated environments.
- Fatty acids, epigenetic mechanisms and chronic diseases: a systematic review(Springer Science and Business Media LLC, 2019) Riezu-Boj, J.I. (José Ignacio); González-Becerra, K. (K.); Martínez-López, E. (E.); Martinez-Climent, J.A. (José Ángel); Barrón-Cabrera, E. (E.); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)Background: Chronic illnesses like obesity, type 2 diabetes (T2D) and cardiovascular diseases, are worldwide major causes of morbidity and mortality. These pathological conditions involve interactions between environmental, genetic, and epigenetic factors. Recent advances in nutriepigenomics are contributing to clarify the role of some nutritional factors, including dietary fatty acids in gene expression regulation. This systematic review assesses currently available information concerning the role of the different fatty acids on epigenetic mechanisms that affect the development of chronic diseases or induce protective effects on metabolic alterations. Methods: A targeted search was conducted in the PubMed/Medline databases using the keywords “fatty acids and epigenetic”. The data were analyzed according to the PRISMA-P guidelines. Results: Consumption fatty acids like n-3 PUFA: EPA and DHA, and MUFA: oleic and palmitoleic acid was associated with an improvement of metabolic alterations. On the other hand, fatty acids that have been associated with the presence or development of obesity, T2D, pro-inflammatory profile, atherosclerosis and IR were n-6 PUFA, saturated fatty acids (stearic and palmitic), and trans fatty acids (elaidic), have been also linked with epigenetic changes. Conclusions: Fatty acids can regulate gene expression by modifying epigenetic mechanisms and consequently result in positive or negative impacts on metabolic outcomes.
- Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake(Wiley Open Access, 2018) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)Introduction: Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hy-pothesized associations of DNA methylation signatures at genes modulating DA sign -aling with obesity features, metabolic profiles, and dietary intake.Methods: An adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened.Results: After applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p <0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (C ACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the pres -ence or absence of abdominal obesity. Pathway analyses revealed a statistically sig-nificant contribution of the aforementioned genes to dopaminergic synapse transmission (p =4.78E−08). Furthermore,SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p <0.001) and carbohydrate (p <0.001) intakes.Conclusions: The results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition.
- DNA methylation in genes of longevity‐regulating pathways: association with obesity and metabolic complications(Impact Journals, LLC, 2019) Santos, J.L. (José Luis); Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Milagro-Yoldi, F.I. (Fermín Ignacio); Salas-Pérez, F. (Francisca); Ramos-López, O. (Omar); Mansego-Talavera, M.L. (María Luisa)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.
- Associations between olfactory pathway gene methylation marks, obesity features and dietary intakes(Springer Science and Business Media LLC, 2019) Santos, J.L. (José Luis); Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Zulet, M.A. (María Ángeles); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)Background: Olfaction is an important sense influencing food preferences, appetite, and eating behaviors. This hypothesis-driven study aimed to assess associations between olfactory pathway gene methylation signatures, obesity features, and dietary intakes. Methods: A nutriepigenomic analysis was conducted in 474 adults from the Methyl Epigenome Network Association (MENA) project. Anthropometric measurements, clinical data, and serum metabolic profiles of the study population were obtained from structured databases of the MENA cohorts. Habitual dietary intake was assessed using a validated semiquantitative food frequency questionnaire. DNA methylation was measured in circulating white blood cells by microarray (Infinium Human Methylation 450 K BeadChips). FDR values (p < 0.0001) were used to select those CpGs that showed the best correlation with body mass index (BMI) and waist circumference (WC). Pathway analyses involving the characterization of genes involved in the olfactory transduction system were performed using KEGG and pathDIP reference databases. Results: Overall, 15 CpG sites at olfactory pathway genes were associated with BMI (p < 0.0001) and WC (p < 0.0001) after adjustments for potential confounding factors. Together, methylation levels at the15 CpG sites accounted for 22% and 20% of the variability in BMI and WC (r 2 = 0.219, p < 0.001, and r 2 = 0.204, p < 0.001, respectively). These genes encompassed olfactory receptors (OR4D2, OR51A7, OR2T34, and OR2Y1) and several downstream signaling molecules (SLC8A1, ANO2, PDE2A, CALML3, GNG7, CALML6, PRKG1, and CAMK2D), which significantly regulated odor detection and signal transduction processes within the complete olfactory cascade, as revealed by pathway enrichment analyses (p = 1.94 × 10–10). Moreover, OR4D2 and OR2Y1 gene methylation patterns strongly correlated with daily intakes of total energy (p < 0.0001), carbohydrates (p < 0.0001), protein (p < 0.0001), and fat (p < 0.0001). Conclusions: The results of this study suggest novel relationships between olfactory pathway gene methylation signatures, obesity indices, and dietary intakes.
- Untargeted metabolomic on urine samples after alpha-lipoic acid and/or eicosapentaenoic acid supplementation in healthy overweight/obese women(BioMed Central, 2018) Martinez, J.A. (José Alfredo); Huerta, A. (Ana); Moreno-Aliaga, M. J. (María Jesús); Gonzalez-Navarro, C.J. (Carlos Javier); Ramos-López, O. (Omar); Romo‐Hualde, A. (Ana)Background: Eicosapentaenoic acid (EPA) and α-lipoic acid (α-LA) have been investigated for their beneficial effects on obesity and cardiovascular risk factors. In the current research, the goal was to evaluate metabolomic changes following the dietary supplementation of these two lipids, alone or combined in healthy overweight/obese sedentary women following an energy-restricted diet. For this purpose, an untargeted metabolomics approach was conducted on urine samples using liquid chromatography coupled with time of flight mass spectrometry (HPLC-TOF-MS). Methods: This is a short-term double blind placebo-controlled study with a parallel nutritional design that lasted 10 weeks. Participants were assigned to one of the 4 experimental groups [Control, EPA (1.3 g/d), α-LA (0.3 g/d) and EPA+α-LA (1.3 g/d + 0.3 g/d)]. All intervention groups followed an energy-restricted diet of 30% less than total energy expenditure. Clinically relevant biochemical measurements were analyzed. Urine samples (24 h) were collected at baseline and after 10 weeks. Untargeted metabolomic analysis on urine samples was carried out, and principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were performed for the pattern recognition and characteristic metabolites identification. Results: Urine samples were scattered in the PCA scores plots in response to the supplementation with α-LA. Totally, 28 putative discriminant metabolites in positive ionization, and 6 in negative ionization were identified among groups clearly differentiated according to the α-LA administration. Remarkably is the presence of an ascorbate intermediate metabolite (one of the isomers of trihydroxy-dioxohexanoate, or dihydroxy–oxohexanedionate) in the groups supplemented with αLA. This fact might be associated with antioxidant properties of both α-LA and ascorbic acid. Correlations between phenotypical parameters and putative metabolites of provided additional information on whether there is a direct or inverse relationship between them. Especially interesting are the negative correlation between ascorbate intermediate metabolite and asymmetric dimethylarginine (ADMA) and the positive one between superoxide dismutase (SOD) and αLA supplementation. Conclusions: This metabolomic approach supports that the beneficial effects of α-LA administration on body weight reduction may be partly explained by the antioxidant properties of this organosulfur carboxylic acid mediated by isomers of trihydroxy-dioxohexanoate, or dihydroxy–oxohexanedionate.
- Prediction of blood lipid phenotypes using obesity-related genetic polymorphisms and lifestyle data in subjects with excessive body weight(Hindawi, 2018) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Goñi-Mateos, L. (Leticia); Milagro-Yoldi, F.I. (Fermín Ignacio); Cuervo, M. (Marta); Ramos-López, O. (Omar)Individual lipid phenotypes including circulating total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) determinations are influenced by gene-environment interactions. The aim of this study was to predict blood lipid level (TC, LDL-c, HDL-c, and TG) variability using genetic and lifestyle data in subjects with excessive body weight-for-height. Methods. This cross-sectional study enrolled 304 unrelated overweight/obese adults of self-reported European ancestry. A total of 95 single nucleotide polymorphisms (SNPs) related to obesity and weight loss were analyzed by a targeted next-generation sequencing system. Relevant genotypes of each SNP were coded as 0 (nonrisk) and 1 (risk). Four genetic risk scores (GRS) for each lipid phenotype were calculated by adding the risk genotypes. Information concerning lifestyle (diet, physical activity, alcohol drinking, and smoking) was obtained using validated questionnaires. Total body fat (TFAT) and visceral fat (VFAT) were determined by dual-energy X-ray absorptiometry. Results. Overall, 45 obesity-related genetic variants were associated with some of the studied blood lipids. In addition to conventional factors (age, sex, dietary intakes, and alcohol consumption), the calculated GRS significantly contributed to explain their corresponding plasma lipid trait. Thus, HDL-c, TG, TC, and LDL-c serum concentrations were predicted by approximately 28% (optimism-corrected adj. R2 = 0 28), 25% (optimism-corrected adj. R2 = 0 25), 24% (optimism-corrected adj. R2 = 0 24), and 21% (optimism-corrected adj. R2 =0.21), respectively. Interestingly, GRS were the greatest contributors to TC (squared partial correlation (PC2 ) = 0.18) and LDL-c (PC2 = 0.18) features. Likewise, VFAT and GRS had a higher impact on HDL-c (PC2 = 0.09 and PC2 = 0.06, respectively) and TG levels (PC2 = 0.20 and PC2 = 0.07, respectively) than the rest of variables. Conclusions. Besides known lifestyle influences, some obesity-related genetic variants could help to predict blood lipid phenotypes.
- Epigenome-wide association study in peripheral white blood cells involving insulin resistance(Springer Nature, 2019) Santos, J.L. (José Luis); Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Milagro-Yoldi, F.I. (Fermín Ignacio); Arpon, A. (Ana); Ramos-López, O. (Omar); Mansego-Talavera, M.L. (María Luisa)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.
- Epigenetic modifications as outcomes of exercise interventions related to specific metabolic alterations: a systematic review(Karger, 2019) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); González-Becerra, K. (K.); Martínez-López, E. (E.); Barrón-Cabrera, E. (E.); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)Background: Chronic diseases arise as a consequence of an unhealthy lifestyle primarily characterized by physical inactivity and unbalanced diets. Regular physical activity can improve health, and there is consistent evidence that these improvements may be the result of epigenetic modifications. Objective: To identify epigenetic modificationsas outcomes of exercise interventions related to specific metabolic alterations. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) methodology for manuscript research and preparation was followed using PubMed and EBSCO databases for literature review. Out of 2,638 articles identified, only 34 articles met the inclusion criteria. Results: The sections of the review were organized by metabolic alterations in which studies were grouped according to healthy, diseased, and trained individuals. Resistance exercise in humans induced epigenetic changes in pathways associated with energy metabolism and insulin sensitivity, contributing to healthy skeletal muscle. Endurance exercise also caused modifications in biomarkers associated to metabolic alterations through changes in DNA methylation and the expression of specific miRNAs. However, both resistance and endurance exercise are necessary to obtain a better physiological adaptation and a combination of both seems to be needed to properly tackle the increasing prevalence of non-communicable pathologies. Conclusion: Given the heterogeneity and complexity of the existing literature, it is currently not possible to propose a specific recommendation about the type, intensity, or duration of exercise that could be beneficial for different subsets of the population (healthy, diseased, and/or trained). Nevertheless, this review highlights the importance of exercise for health and shows the need to perform more research in this emerging area to identify epigenetic biomarkers that could serve as indicators of exercise adaptations.