Metabolite profiling reveals new insights into the regulation of serum urate in humans.
Serum urate, the final breakdown product of purine metabolism, is causally involved in the pathogenesis of gout, and implicated in cardiovascular disease and type 2 diabetes. Serum urate levels highly differ between men and women; however the underlying biological processes in its regulation are still not completely understood and are assumed to result from a complex interplay between genetic, environmental and lifestyle factors. In order to describe the metabolic vicinity of serum urate, we analyzed 355 metabolites in 1,764 individuals of the population-based KORA F4 study and constructed a metabolite network around serum urate using Gaussian Graphical Modeling in a hypothesis-free approach. We subsequently investigated the effect of sex and urate lowering medication on all 38 metabolites assigned to the network. Within the resulting network three main clusters could be detected around urate, including the well-known pathway of purine metabolism, as well as several dipeptides, a group of essential amino acids, and a group of steroids. Of the 38 assigned metabolites, 25 showed strong differences between sexes. Association with uricostatic medication intake was not only confined to purine metabolism but seen for seven metabolites within the network. Our findings highlight pathways that are important in the regulation of serum urate and suggest that dipeptides, amino acids, and steroid hormones are playing a role in its regulation. The findings might have an impact on the development of specific targets in the treatment and prevention of hyperuricemia.
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Eva
E
Albrecht
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Melanie
M
Waldenberger
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Jan
J
Krumsiek
Metabolon, Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 USA.
Anne M
AM
Evans
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Ulli
U
Jeratsch
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Michaela
M
Breier
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Lehrstuhl für Experimentelle Genetik, Technische Universität München, Munich, Germany.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany.
Jerzy
J
Adamski
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.
Wolfgang
W
Koenig
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Sonja
S
Zeilinger
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Christiane
C
Fuchs
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Hanover Unified Biobank, Hanover Medical School, Hanover, Germany.
Norman
N
Klopp
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Fabian J
FJ
Theis
Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry, and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.|Klinikum Grosshadern, Munich, Germany.
H-Erich
HE
Wichmann
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City-Qatar Foundation, Doha, Qatar.
Karsten
K
Suhre
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Hanover Unified Biobank, Hanover Medical School, Hanover, Germany.
Thomas
T
Illig
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.|Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Konstantin
K
Strauch
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Munich Heart Alliance, Munich, Germany.
Annette
A
Peters
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Christian
C
Gieger
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Gabi
G
Kastenmüller
Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Angela
A
Doering
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Central Hospital of Augsburg, Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Research in the Region of Augsburg Myocardial Infarction Registry, Augsburg, Germany.
Christa
C
Meisinger
Allopurinol; Gaussian Graphical Modeling; Metabolite network; Pathway reconstruction; Purine metabolism; Uric acid