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

TL;DR

This study explores how dicarbonyl compounds like methylglyoxal and glyoxal are linked to health traits such as kidney function and enzyme activity in a large population.

Contribution

The study provides the first phenome-wide and genome-wide associations of dicarbonyls in a population-based setting.

Findings

Dicarbonyls are strongly associated with glomerular filtration rate and gamma-glutamyltransferase activity.

3-deoxyglucosone is linked to glucose levels and a specific genetic variant in NFKBIA.

Abstract

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.

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.

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.

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.

10.13039/501100001659Deutsche Forschungsgemeinschaft, Helmholtz Munich, 10.13039/100010447German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF).

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