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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

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).

Originalsprache	Englisch
Aufsatznummer	105007
Zeitschrift	eBioMedicine
Jahrgang	101
Seiten (von - bis)	105007
DOIs	https://doi.org/10.1016/j.ebiom.2024.105007
Publikationsstatus	Veröffentlicht - 03.2024

Fördermittel

We thank all participants for their long-term commitment to the KORA and BiDirect studies, the staff of the studies for design, data collection, and management. The KORA study ( https://www.helmholtz-munich.de/en/epi/cohort/kora ) was initiated and financed by Helmholtz Munich which is funded by the German Federal Ministry of Education and Research BMBF and by the State of Bavaria . Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg. The BiDirect Study ( https://www.medizin.uni-muenster.de/en/epi/research/projects/bidirect.html ) is supported by grants of the German Ministry of Research and Education BMBF to the University of Muenster ( 01ER0816 and 01ER1506 ). Furthermore, this work was supported by grants from the German Centre for Cardiovascular Research DZHK to MS ( 81Z0700109 ) and from the Deutsche Forschungsgemeinschaft (DFG) to TF and PPN. We also thank Christine Eichholz from the Bioanalytic Core facility ( University of Lübeck ) for her support during sample preparation and extraction. Deutsche Forschungsgemeinschaft, Helmholtz Munich, German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF).We thank all participants for their long-term commitment to the KORA and BiDirect studies, the staff of the studies for design, data collection, and management. The KORA study (https://www.helmholtz-munich.de/en/epi/cohort/kora) was initiated and financed by Helmholtz Munich which is funded by the German Federal Ministry of Education and Research BMBF and by the State of Bavaria. Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg. The BiDirect Study (https://www.medizin.uni-muenster.de/en/epi/research/projects/bidirect.html) is supported by grants of the German Ministry of Research and Education BMBF to the University of Muenster (01ER0816 and 01ER1506). Furthermore, this work was supported by grants from the German Centre for Cardiovascular Research DZHK to MS (81Z0700109) and from the Deutsche Forschungsgemeinschaft (DFG) to TF and PPN. We also thank Christine Eichholz from the Bioanalytic Core facility (University of Lübeck) for her support during sample preparation and extraction.

Träger	Trägernummer
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

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

DFG-Fachsystematik

2.22-09 Pharmakologie

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10.1016/j.ebiom.2024.105007

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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. (2024). Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activity. eBioMedicine, 101, 105007. Artikel 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, Jg. 101, 105007, S. 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

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Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

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