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

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^*

^*Corresponding author for this work

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).

Original language	English
Article number	105007
Journal	eBioMedicine
Volume	101
Pages (from-to)	105007
DOIs	https://doi.org/10.1016/j.ebiom.2024.105007
Publication status	Published - 03.2024

Funding

Funders	Funder number
German Centre for Cardiovascular Research (DZHK)	81Z0700109
German Ministry of Research and Education BMBF
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
University of Muenster	01ER0816, 01ER1506
Deutsches Zentrum für Herz-Kreislaufforschung
Deutsche Forschungsgemeinschaft
Bundesministerium für Bildung und Forschung

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

2.22-09 Pharmacology

Access to Document

10.1016/j.ebiom.2024.105007

Cite this

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. (2024). Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activity. eBioMedicine, 101, 105007. Article 105007. https://doi.org/10.1016/j.ebiom.2024.105007

@article{20f346439c624822b62603a573a6b946,

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

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).",

author = "Philip Harrer and Julica Inderhees and Chen Zhao and Barbara Schormair and Erik Tilch and Christian Gieger and Annette Peters and Olaf J{\"o}hren and Thomas Fleming and Nawroth, \{Peter P.\} and Klaus Berger and Marco Hermesdorf and Juliane Winkelmann and Markus Schwaninger and Konrad Oexle",

year = "2024",

month = mar,

doi = "10.1016/j.ebiom.2024.105007",

language = "English",

volume = "101",

pages = "105007",

journal = "eBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

Harrer, P, Inderhees, J, Zhao, C, Schormair, B, Tilch, E, Gieger, C, Peters, A, Jöhren, O, Fleming, T, Nawroth, PP, Berger, K, Hermesdorf, M, Winkelmann, J, Schwaninger, M & Oexle, K 2024, 'Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activity', eBioMedicine, vol. 101, 105007, pp. 105007. https://doi.org/10.1016/j.ebiom.2024.105007

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

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).

UR - https://www.scopus.com/pages/publications/85185181783

UR - https://www.mendeley.com/catalogue/2a3a82f6-48d6-36b1-a7f9-4811b9f73aad/

U2 - 10.1016/j.ebiom.2024.105007

DO - 10.1016/j.ebiom.2024.105007

M3 - Journal articles

C2 - 38354534

AN - SCOPUS:85185181783

SN - 2352-3964

VL - 101

SP - 105007

JO - eBioMedicine

JF - eBioMedicine

M1 - 105007

ER -

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

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

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