The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study

PLoS One. 2016 Apr 27;11(4):e0153163. doi: 10.1371/journal.pone.0153163. eCollection 2016.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Antihypertensive Agents / therapeutic use
  • Blood Pressure / drug effects
  • Blood Pressure / genetics
  • Dipeptides / metabolism
  • Female
  • Genetic Variation / drug effects
  • Genetic Variation / genetics
  • Genotype
  • Humans
  • Hypertension / drug therapy
  • Hypertension / genetics
  • Hypertension / metabolism
  • Male
  • Metabolome / drug effects*
  • Metabolome / genetics*
  • Metabolomics / methods
  • Middle Aged
  • Oligopeptides / metabolism
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism*
  • Pharmacogenetics / methods


  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Dipeptides
  • Oligopeptides
  • aspartyl-phenylalanine
  • phenylalanylserine
  • Peptidyl-Dipeptidase A

Grant support

The KORA research platform is financed by the Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria. This study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF; to the German Center for Diabetes Research (DZD e.V.; and by the Helmholtz Cross Program Initiative “Personalized Medicine (iMed)”. The research leading to these results has partly received funding from the European Union's Seventh Framework Programme (FP7-Health-F5-2012) under grant agreement n° 305280 (MIMOmics; It was also supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant 01ZX1313A-2014; K.S. is supported by “Biomedical Research Program” funds at Weill Cornell Medical College in Qatar, a program funded by the Qatar Foundation ( TwinsUK was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013; The study also receives support from the National Institute for Health Research (NIHR; - funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute ( and National Eye Institute ( via NIH/CIDR. Metabolomic analysis was funded by Pfizer ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.