TY - JOUR
T1 - Phenotypic and genome-wide studies on dicarbonyls
T2 - major associations to glomerular filtration rate and gamma-glutamyltransferase activity
AU - Harrer, Philip
AU - Inderhees, Julica
AU - Zhao, Chen
AU - Schormair, Barbara
AU - Tilch, Erik
AU - Gieger, Christian
AU - Peters, Annette
AU - Jöhren, Olaf
AU - Fleming, Thomas
AU - Nawroth, Peter P.
AU - Berger, Klaus
AU - Hermesdorf, Marco
AU - Winkelmann, Juliane
AU - Schwaninger, Markus
AU - Oexle, Konrad
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/3
Y1 - 2024/3
N2 - 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).
AB - 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).
KW - Dicarbonyl compounds
KW - Genome-wide association study
KW - Glucose
KW - Kidney function
KW - Liver enzymes
KW - Phenotypic association study
UR - http://www.scopus.com/inward/record.url?scp=85185181783&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2024.105007
DO - 10.1016/j.ebiom.2024.105007
M3 - Article
AN - SCOPUS:85185181783
SN - 2352-3964
VL - 101
JO - eBioMedicine
JF - eBioMedicine
M1 - 105007
ER -