Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in context
Summary: Background: The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, respectively, have not been provided. M...
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Elsevier
2024-03-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424000422 |
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| author | Philip Harrer Julica Inderhees Chen Zhao Barbara Schormair Erik Tilch Christian Gieger Annette Peters Olaf Jöhren Thomas Fleming Peter P. Nawroth Klaus Berger Marco Hermesdorf Juliane Winkelmann Markus Schwaninger Konrad Oexle |
| author_facet | Philip Harrer Julica Inderhees Chen Zhao Barbara Schormair Erik Tilch Christian Gieger Annette Peters Olaf Jöhren Thomas Fleming Peter P. Nawroth Klaus Berger Marco Hermesdorf Juliane Winkelmann Markus Schwaninger Konrad Oexle |
| author_sort | Philip Harrer |
| collection | DOAJ |
| description | Summary: Background: The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, respectively, have not been provided. Methods: MG, GO and 3-DG were measured by LC-MS in 1304 serum samples of two populations (KORA, n = 482; BiDirect, n = 822) and assessed for associations with genome-wide SNPs (GWAS) and with phenome-wide traits. Redundancy analysis (RDA) was used to identify major independent trait associations. Findings: Mutual correlations of dicarbonyls were highly significant, being stronger between MG and GO (ρ = 0.6) than between 3-DG and MG or GO (ρ = 0.4). Significant phenotypic results included associations of all dicarbonyls with sex, waist-to-hip ratio, glomerular filtration rate (GFR), gamma-glutamyltransferase (GGT), and hypertension, of MG and GO with age and C-reactive protein, of GO and 3-DG with glucose and antidiabetics, of MG with contraceptives, of GO with ferritin, and of 3-DG with smoking. RDA revealed GFR, GGT and, in case of 3-DG, glucose as major contributors to dicarbonyl variance. GWAS did not identify genome-wide significant loci. SNPs previously associated with glyoxalase activity did not reach nominal significance. When multiple testing was restricted to the lead SNPs of GWASs on the traits selected by RDA, 3-DG was found to be associated (p = 2.3 × 10−5) with rs1741177, an eQTL of NF-κB inhibitor NFKBIA. Interpretation: This large-scale, population-based study has identified numerous associations, with GFR and GGT being of pivotal importance, providing unbiased perspectives on dicarbonyls beyond the current state. Funding: Deutsche Forschungsgemeinschaft, Helmholtz Munich, German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF). |
| first_indexed | 2024-03-08T00:49:26Z |
| format | Article |
| id | doaj.art-c87523ca0c424d7f8f197fe4dbad99de |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-08T00:49:26Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-c87523ca0c424d7f8f197fe4dbad99de2024-02-15T05:24:27ZengElsevierEBioMedicine2352-39642024-03-01101105007Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in contextPhilip Harrer0Julica Inderhees1Chen Zhao2Barbara Schormair3Erik Tilch4Christian Gieger5Annette Peters6Olaf Jöhren7Thomas Fleming8Peter P. Nawroth9Klaus Berger10Marco Hermesdorf11Juliane Winkelmann12Markus Schwaninger13Konrad Oexle14Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lubeck, Lubeck, Germany; Bioanalytic Core Facility, Center for Brain, Behavior and Metabolism, University of Lübeck, Germany; German Centre for Cardiovascular Research (DZHK), Hamburg-Lübeck-Kiel, GermanyInstitute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, GermanyInstitute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, GermanyInstitute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, GermanyResearch Unit of Molecular Epidemiology, Helmholtz Munich, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Munich, Neuherberg, GermanyInstitute of Epidemiology, Helmholtz Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Chair of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lubeck, Lubeck, Germany; Bioanalytic Core Facility, Center for Brain, Behavior and Metabolism, University of Lübeck, GermanyDepartment of Internal Medicine, University of Heidelberg, Heidelberg, GermanyDepartment of Internal Medicine, University of Heidelberg, Heidelberg, GermanyInstitute of Epidemiology and Social Medicine, University of Münster, Münster, GermanyInstitute of Epidemiology and Social Medicine, University of Münster, Münster, GermanyInstitute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Centre for Mental Health (DZPG), Munich-Augsburg, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lubeck, Lubeck, Germany; German Centre for Cardiovascular Research (DZHK), Hamburg-Lübeck-Kiel, GermanyInstitute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Corresponding author. Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany.Summary: Background: The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, respectively, have not been provided. Methods: MG, GO and 3-DG were measured by LC-MS in 1304 serum samples of two populations (KORA, n = 482; BiDirect, n = 822) and assessed for associations with genome-wide SNPs (GWAS) and with phenome-wide traits. Redundancy analysis (RDA) was used to identify major independent trait associations. Findings: Mutual correlations of dicarbonyls were highly significant, being stronger between MG and GO (ρ = 0.6) than between 3-DG and MG or GO (ρ = 0.4). Significant phenotypic results included associations of all dicarbonyls with sex, waist-to-hip ratio, glomerular filtration rate (GFR), gamma-glutamyltransferase (GGT), and hypertension, of MG and GO with age and C-reactive protein, of GO and 3-DG with glucose and antidiabetics, of MG with contraceptives, of GO with ferritin, and of 3-DG with smoking. RDA revealed GFR, GGT and, in case of 3-DG, glucose as major contributors to dicarbonyl variance. GWAS did not identify genome-wide significant loci. SNPs previously associated with glyoxalase activity did not reach nominal significance. When multiple testing was restricted to the lead SNPs of GWASs on the traits selected by RDA, 3-DG was found to be associated (p = 2.3 × 10−5) with rs1741177, an eQTL of NF-κB inhibitor NFKBIA. Interpretation: This large-scale, population-based study has identified numerous associations, with GFR and GGT being of pivotal importance, providing unbiased perspectives on dicarbonyls beyond the current state. Funding: Deutsche Forschungsgemeinschaft, Helmholtz Munich, German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF).http://www.sciencedirect.com/science/article/pii/S2352396424000422Dicarbonyl compoundsPhenotypic association studyGenome-wide association studyKidney functionLiver enzymesGlucose |
| spellingShingle | Philip Harrer Julica Inderhees Chen Zhao Barbara Schormair Erik Tilch Christian Gieger Annette Peters Olaf Jöhren Thomas Fleming Peter P. Nawroth Klaus Berger Marco Hermesdorf Juliane Winkelmann Markus Schwaninger Konrad Oexle Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in context EBioMedicine Dicarbonyl compounds Phenotypic association study Genome-wide association study Kidney function Liver enzymes Glucose |
| title | Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in context |
| title_full | Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in context |
| title_fullStr | Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in context |
| title_full_unstemmed | Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in context |
| title_short | Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activityResearch in context |
| title_sort | phenotypic and genome wide studies on dicarbonyls major associations to glomerular filtration rate and gamma glutamyltransferase activityresearch in context |
| topic | Dicarbonyl compounds Phenotypic association study Genome-wide association study Kidney function Liver enzymes Glucose |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424000422 |
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