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

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

doi:10.1016/j.ebiom.2024.105007

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

EBioMedicine. 2024 Mar:101:105007. doi: 10.1016/j.ebiom.2024.105007. Epub 2024 Feb 13.

Authors

Affiliations

¹ Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany.
² Institute 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, Germany.
³ Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany.
⁴ Research Unit of Molecular Epidemiology, Helmholtz Munich, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Munich, Neuherberg, Germany.
⁵ Institute 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, Germany.
⁶ Institute 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.
⁷ Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany.
⁸ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
⁹ Institute 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, Germany.
¹⁰ Institute 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, Germany.
¹¹ Institute 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. Electronic address: [email protected].

Abstract

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).

Keywords: Dicarbonyl compounds; Genome-wide association study; Glucose; Kidney function; Liver enzymes; Phenotypic association study.

MeSH terms

Genome-Wide Association Study*
Glomerular Filtration Rate
Glucose
Glyoxal / metabolism
Humans
Polymorphism, Single Nucleotide
Pyruvaldehyde / metabolism
gamma-Glutamyltransferase*

Substances

gamma-Glutamyltransferase
Pyruvaldehyde
Glyoxal
Glucose