The pharmacogenetic footprint of ACE inhibition: A population-based metabolomics study

Elisabeth Altmaier; Cristina Menni; Margit Heier; Christa Meisinger; Barbara Thorand; Jan Quell; Michael Kobl; Werner Römisch-Margl; Ana M. Valdes; Massimo Mangino; Melanie Waldenberger; Konstantin Strauch; Thomas Illig; Jerzy Adamski; Tim Spector; Christian Gieger; Karsten Suhre; Gabi Kastenmüller

doi:10.1371/journal.pone.0153163

The pharmacogenetic footprint of ACE inhibition: A population-based metabolomics study

Elisabeth Altmaier, Cristina Menni, Margit Heier, Christa Meisinger, Barbara Thorand, Jan Quell, Michael Kobl, Werner Römisch-Margl, Ana M. Valdes, Massimo Mangino, Melanie Waldenberger, Konstantin Strauch, Thomas Illig, Jerzy Adamski, Tim Spector, Christian Gieger, Karsten Suhre, Gabi Kastenmüller

Twin Research & Genetic Epidemiology

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Abstract

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.

Original language	English
Article number	e0153163
Journal	PL o S One
Volume	11
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0153163
Publication status	Published - 27 Apr 2016

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10.1371/journal.pone.0153163Licence: CC BY

ThepharmacogeneticfootprintofACE_ALTMAIERAccepted7March2016_GOLDFPVFinal published version, 745 KBLicence: CC BY

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Altmaier, E., Menni, C., Heier, M., Meisinger, C., Thorand, B., Quell, J., Kobl, M., Römisch-Margl, W., Valdes, A. M., Mangino, M., Waldenberger, M., Strauch, K., Illig, T., Adamski, J., Spector, T., Gieger, C., Suhre, K., & Kastenmüller, G. (2016). The pharmacogenetic footprint of ACE inhibition: A population-based metabolomics study. PL o S One , 11(4), Article e0153163. https://doi.org/10.1371/journal.pone.0153163

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title = "The pharmacogenetic footprint of ACE inhibition: A population-based metabolomics study",

abstract = "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.",

author = "Elisabeth Altmaier and Cristina Menni and Margit Heier and Christa Meisinger and Barbara Thorand and Jan Quell and Michael Kobl and Werner R{\"o}misch-Margl and Valdes, {Ana M.} and Massimo Mangino and Melanie Waldenberger and Konstantin Strauch and Thomas Illig and Jerzy Adamski and Tim Spector and Christian Gieger and Karsten Suhre and Gabi Kastenm{\"u}ller",

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Altmaier, E, Menni, C, Heier, M, Meisinger, C, Thorand, B, Quell, J, Kobl, M, Römisch-Margl, W, Valdes, AM, Mangino, M, Waldenberger, M, Strauch, K, Illig, T, Adamski, J, Spector, T, Gieger, C, Suhre, K & Kastenmüller, G 2016, 'The pharmacogenetic footprint of ACE inhibition: A population-based metabolomics study', PL o S One , vol. 11, no. 4, e0153163. https://doi.org/10.1371/journal.pone.0153163

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T1 - The pharmacogenetic footprint of ACE inhibition

T2 - A population-based metabolomics study

AU - Altmaier, Elisabeth

AU - Menni, Cristina

AU - Heier, Margit

AU - Meisinger, Christa

AU - Thorand, Barbara

AU - Quell, Jan

AU - Kobl, Michael

AU - Römisch-Margl, Werner

AU - Valdes, Ana M.

AU - Mangino, Massimo

AU - Waldenberger, Melanie

AU - Strauch, Konstantin

AU - Illig, Thomas

AU - Adamski, Jerzy

AU - Spector, Tim

AU - Gieger, Christian

AU - Suhre, Karsten

AU - Kastenmüller, Gabi

PY - 2016/4/27

Y1 - 2016/4/27

N2 - 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.

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The pharmacogenetic footprint of ACE inhibition: A population-based metabolomics study

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