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Harrer, P. ; Inderhees, J.* ; Zhao, C. ; Schormair, B. ; Tilch, E. ; Gieger, C. ; Peters, A. ; Jöhren, O.* ; Fleming, T.* ; Nawroth, P.P.* ; Berger, K.* ; Hermesdorf, M.* ; Winkelmann, J. ; Schwaninger, M.* ; Oexle, K.

Phenotypic and genome-wide studies on dicarbonyls: Major associations to glomerular filtration rate and gamma-glutamyltransferase activity.

EBioMedicine 101:105007 (2024)

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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).

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Dicarbonyl Compounds ; Genome-wide Association Study ; Glucose ; Kidney Function ; Liver Enzymes ; Phenotypic Association Study; Genetic Association; Glyoxalase System; Methylglyoxal; Cell; Stress; Identification; Impairs; Stroke; Risk; G5pr

ISSN (print) / ISBN 2352-3964

e-ISSN 2352-3964

Journal EBioMedicine

Quellenangaben Volume: 101, Article Number: 105007

Publisher Elsevier

Publishing Place Amsterdam [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)
Institute of Epidemiology (EPI)

Grants German Federal Ministry of Research and Education (BMBF)
German Centre for Cardiovascular Research(DZHK)
Helmholtz Munich
Deutsche Forschungsgemeinschaft