The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.
Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them-and perhaps also the other dipeptides-as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity.
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Elisabeth
E
Altmaier
Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, United Kingdom.
Cristina
C
Menni
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Margit
M
Heier
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Christa
C
Meisinger
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Barbara
B
Thorand
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Jan
J
Quell
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Michael
M
Kobl
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Werner
W
Römisch-Margl
Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, United Kingdom.
Ana M
AM
Valdes
Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, United Kingdom.
Massimo
M
Mangino
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Melanie
M
Waldenberger
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Marchionistr. 15, D-81377 München, Germany.
Konstantin
K
Strauch
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.|Hannover Unified Biobank, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.|Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hanover, Germany.
Thomas
T
Illig
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.|Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, D-85354 Freising, Germany.|German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Jerzy
J
Adamski
Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, United Kingdom.
Tim
T
Spector
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Christian
C
Gieger
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.|Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, PO Box 24144, Doha, State of Qatar.
Karsten
K
Suhre
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.|Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, United Kingdom.|German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Gabi
G
Kastenmüller
D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D004151:Dipeptides / Q000378:metabolism; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000187:drug effects* / Q000235:genetics*; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D009842:Oligopeptides / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004151:Dipeptides; D009842:Oligopeptides; C045207:aspartyl-phenylalanine; C025275:phenylalanylserine; D007703:Peptidyl-Dipeptidase A