Gutierrez-Repiso, CarolinaLinares-Pineda, Teresa MariaGonzalez-Jimenez, AndresAguilar-Lineros, FranciscaValdes, SergioSoriguer, FedericoRojo-Martinez, GemmaTinahones, Francisco J.Morcillo, Sonsoles2022-10-072022-10-072021-09-27Gutiérrez-Repiso C, Linares-Pineda TM, Gonzalez-Jimenez A, Aguilar-Lineros F, Valdés S, Soriguer F, et al. Epigenetic Biomarkers of Transition from Metabolically Healthy Obesity to Metabolically Unhealthy Obesity Phenotype: A Prospective Study. Int J Mol Sci. 2021 Sep 27;22(19):10417.http://hdl.handle.net/10668/4243Background: Identifying those parameters that could potentially predict the deterioration of metabolically healthy phenotype is a matter of debate. In this field, epigenetics, in particular DNA methylation deserves special attention. Results: The aim of the present study was to analyze the long-term evolution of methylation patterns in a subset of metabolically healthy subjects in order to search for epigenetic markers that could predict the progression to an unhealthy state. Twenty-six CpG sites were significantly differentially methylated, both at baseline and 11-year follow-up. These sites were related to 19 genes or pseudogenes; a more in-depth analysis of the methylation sites of these genes showed that CYP2E1 had 50% of the collected CpG sites differently methylated between stable metabolically healthy obesity (MHO) and unstable MHO, followed by HLA-DRB1 (33%), ZBTB45 (16%), HOOK3 (14%), PLCZ1 (14%), SLC1A1 (12%), MUC2 (12%), ZFPM2 (12.5%) and HLA-DQB2 (8%). Pathway analysis of the selected 26 CpG sites showed enrichment in pathways linked to th1 and th2 activation, antigen presentation, allograft rejection signals and metabolic processes. Higher methylation levels in the cg20707527 (ZFPM2) could have a protective effect against the progression to unstable MHO (OR: 0.21, 95%CI (0.067–0.667), p < 0.0001), whilst higher methylation levels in cg11445109 (CYP2E1) would increase the progression to MUO; OR: 2.72, 95%CI (1.094–6.796), p < 0.0014; respectively). Conclusions: DNA methylation status is associated with the stability/worsening of MHO phenotype. Two potential biomarkers of the transition to an unhealthy state were identified and deserve further investigation (cg20707527 and cg11445109). Moreover, the described differences in methylation could alter immune system-related pathways, highlighting these pathways as therapeutic targets to prevent metabolic deterioration in MHO patients.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Metabolically healthy obesityEpigenetic biomarkersMetabolic syndromeDNA methylationImmune systemMedical Subject Headings::Persons::Persons::Age Groups::AdolescentMedical Subject Headings::Persons::Persons::Age Groups::AdultMedical Subject Headings::Persons::Persons::Age Groups::Adult::AgedMedical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, PharmacologicalMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Follow-Up StudiesMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Persons::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective StudiesMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Base Sequence::GC Rich Sequence::CpG IslandsMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Alkylation::Methylation::DNA MethylationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, GeneticMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::ObesityMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Cytochromes::Cytochrome P-450 Enzyme System::Aryl Hydrocarbon Hydroxylases::Cytochrome P-450 CYP2E1Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Histocompatibility Antigens Class II::HLA-D Antigens::HLA-DR Antigens::HLA-DR beta-Chains::HLA-DRB1 ChainsMedical Subject Headings::Phenomena and Processes::Immune System Phenomena::Immune System Processes::Antigen PresentationMedical Subject Headings::Persons::Persons::Volunteers::Healthy VolunteersMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::PseudogenesMedical Subject Headings::Anatomy::Hemic and Immune Systems::Immune Systemresearch article34638758open accessBiomarcadoresSíndrome metabólicoMetilación de ADNSistema inmunológico10.3390/ijms2219104171422-0067PMC8508854