TY - JOUR
T1 - Metabolite profiling reveals new insights into the regulation of serum urate in humans
AU - Albrecht, Eva
AU - Waldenberger, Melanie
AU - Krumsiek, Jan
AU - Evans, Anne M.
AU - Jeratsch, Ulli
AU - Breier, Michaela
AU - Adamski, Jerzy
AU - Koenig, Wolfgang
AU - Zeilinger, Sonja
AU - Fuchs, Christiane
AU - Klopp, Norman
AU - Theis, Fabian J.
AU - Wichmann, H. Erich
AU - Suhre, Karsten
AU - Illig, Thomas
AU - Strauch, Konstantin
AU - Peters, Annette
AU - Gieger, Christian
AU - Kastenmüller, Gabi
AU - Doering, Angela
AU - Meisinger, Christa
N1 - Funding Information:
Acknowledgments The KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Max-imilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7-Health-F5-2012) under grant agreement no 305280 (MIMOmics). We thank all KORA study participants and all members of the field staff in Augsburg who planned and conducted the study. KS is supported by ‘Biomedical Research Program’ funds at Weill Cornell Medical College in Qatar, a program funded by the Qatar Foundation. Part of the study was supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center Diabetes Research (DZD e.V.). The statements made herein are solely the responsibility of the authors.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Allopurinol
KW - Gaussian Graphical Modeling
KW - Metabolite network
KW - Pathway reconstruction
KW - Purine metabolism
KW - Uric acid
UR - http://www.scopus.com/inward/record.url?scp=84892483679&partnerID=8YFLogxK
U2 - 10.1007/s11306-013-0565-2
DO - 10.1007/s11306-013-0565-2
M3 - Article
AN - SCOPUS:84892483679
SN - 1573-3882
VL - 10
SP - 141
EP - 151
JO - Metabolomics
JF - Metabolomics
IS - 1
ER -