Publication: Epigenetic Biomarkers of Transition from Metabolically Healthy Obesity to Metabolically Unhealthy Obesity Phenotype: A Prospective Study
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Date
2021-09-27
Authors
Gutiérrez-Repiso, Carolina
Linares-Pineda, Teresa María
Gonzalez-Jimenez, Andres
Aguilar-Lineros, Francisca
Valdés, Sergio
Soriguer, Federico
Rojo-Martínez, Gemma
Tinahones, Francisco J.
Morcillo, Sonsoles
Advisors
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MDPI
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Abstract
Background: 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.
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MeSH Terms
Medical Subject Headings::Persons::Persons::Age Groups::Adolescent
Medical Subject Headings::Persons::Persons::Age Groups::Adult
Medical Subject Headings::Persons::Persons::Age Groups::Adult::Aged
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological
Medical Subject Headings::Check Tags::Female
Medical 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 Studies
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Persons::Persons::Age Groups::Adult::Middle Aged
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype
Medical 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 Studies
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Base Sequence::GC Rich Sequence::CpG Islands
Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Alkylation::Methylation::DNA Methylation
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Cytochromes::Cytochrome P-450 Enzyme System::Aryl Hydrocarbon Hydroxylases::Cytochrome P-450 CYP2E1
Medical 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 Chains
Medical Subject Headings::Phenomena and Processes::Immune System Phenomena::Immune System Processes::Antigen Presentation
Medical Subject Headings::Persons::Persons::Volunteers::Healthy Volunteers
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Pseudogenes
Medical Subject Headings::Anatomy::Hemic and Immune Systems::Immune System
Medical Subject Headings::Persons::Persons::Age Groups::Adult
Medical Subject Headings::Persons::Persons::Age Groups::Adult::Aged
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological
Medical Subject Headings::Check Tags::Female
Medical 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 Studies
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Persons::Persons::Age Groups::Adult::Middle Aged
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype
Medical 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 Studies
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Base Sequence::GC Rich Sequence::CpG Islands
Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Alkylation::Methylation::DNA Methylation
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Cytochromes::Cytochrome P-450 Enzyme System::Aryl Hydrocarbon Hydroxylases::Cytochrome P-450 CYP2E1
Medical 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 Chains
Medical Subject Headings::Phenomena and Processes::Immune System Phenomena::Immune System Processes::Antigen Presentation
Medical Subject Headings::Persons::Persons::Volunteers::Healthy Volunteers
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Pseudogenes
Medical Subject Headings::Anatomy::Hemic and Immune Systems::Immune System
DeCS Terms
CIE Terms
Keywords
Metabolically healthy obesity, Epigenetic biomarkers, Metabolic syndrome, DNA methylation, Immune system, Obesidad metabólica benigna, Biomarcadores, Síndrome metabólico, Metilación de ADN, Sistema inmunológico
Citation
Gutiérrez-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.