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 product...
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| creator | Altmaier, Elisabeth Menni, Cristina Heier, Margit Meisinger, Christa Thorand, Barbara Quell, Jan Kobl, Michael Römisch-Margl, Werner Valdes, Ana M Mangino, Massimo Waldenberger, Melanie Strauch, Konstantin Illig, Thomas Adamski, Jerzy Spector, Tim Gieger, Christian Suhre, Karsten Kastenmüller, Gabi |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0153163 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0153163</identifier><identifier>PMID: 27120469</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ACE protein ; Adult ; Aged ; Agent Orange ; Angiotensin-converting enzyme inhibitors ; Angiotensin-Converting Enzyme Inhibitors - therapeutic use ; Antihypertensive agents ; Antihypertensive Agents - therapeutic use ; Antihypertensives ; Bioinformatics ; Biology ; Biology and Life Sciences ; Blood ; Blood levels ; Blood pressure ; Blood Pressure - drug effects ; Blood Pressure - genetics ; Cardiovascular diseases ; Chemical industry ; Diabetes ; Dipeptides - metabolism ; Environmental health ; Enzymes ; Epidemiology ; Female ; Genetic diversity ; Genetic variance ; Genetic Variation - drug effects ; Genetic Variation - genetics ; Genetics ; Genomes ; Genotype ; Genotypes ; Health aspects ; Heterozygotes ; Homozygotes ; Humans ; Hypertension ; Hypertension - drug therapy ; Hypertension - genetics ; Hypertension - metabolism ; Inhibitors ; Loci ; Male ; Mass spectrometry ; Medical research ; Medicine and health sciences ; Metabolism ; Metabolites ; Metabolome - drug effects ; Metabolome - genetics ; Metabolomics ; Metabolomics - methods ; Middle Aged ; Narcotics ; Oligopeptides ; Oligopeptides - metabolism ; Peptides ; Peptidyl-Dipeptidase A - genetics ; Peptidyl-Dipeptidase A - metabolism ; Pharmacogenetics - methods ; Pharmacology ; Physical Sciences ; Physiology ; Polypeptides ; Population studies ; Population-based studies ; Research and Analysis Methods ; Risk factors ; Scientific imaging ; Studies ; Substrates</subject><ispartof>PloS one, 2016-04, Vol.11 (4), p.e0153163</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Altmaier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>ACE protein</subject><subject>Adult</subject><subject>Aged</subject><subject>Agent Orange</subject><subject>Angiotensin-converting enzyme inhibitors</subject><subject>Angiotensin-Converting Enzyme Inhibitors - therapeutic use</subject><subject>Antihypertensive agents</subject><subject>Antihypertensive Agents - therapeutic use</subject><subject>Antihypertensives</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Blood</subject><subject>Blood levels</subject><subject>Blood pressure</subject><subject>Blood Pressure - drug effects</subject><subject>Blood Pressure - genetics</subject><subject>Cardiovascular diseases</subject><subject>Chemical industry</subject><subject>Diabetes</subject><subject>Dipeptides - metabolism</subject><subject>Environmental health</subject><subject>Enzymes</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Genetic Variation - drug effects</subject><subject>Genetic Variation - genetics</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Health aspects</subject><subject>Heterozygotes</subject><subject>Homozygotes</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypertension - drug therapy</subject><subject>Hypertension - genetics</subject><subject>Hypertension - metabolism</subject><subject>Inhibitors</subject><subject>Loci</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Medical research</subject><subject>Medicine and health 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Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study</title><author>Altmaier, Elisabeth ; Menni, Cristina ; Heier, Margit ; Meisinger, Christa ; Thorand, Barbara ; Quell, Jan ; Kobl, Michael ; Römisch-Margl, Werner ; Valdes, Ana M ; Mangino, Massimo ; Waldenberger, Melanie ; Strauch, Konstantin ; Illig, Thomas ; Adamski, Jerzy ; Spector, Tim ; Gieger, Christian ; Suhre, Karsten ; Kastenmüller, Gabi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-4f15489674dc373807b48ff5934a5bc4128870373e0722dfb34c74f5818f36f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>ACE protein</topic><topic>Adult</topic><topic>Aged</topic><topic>Agent Orange</topic><topic>Angiotensin-converting enzyme inhibitors</topic><topic>Angiotensin-Converting Enzyme Inhibitors - therapeutic use</topic><topic>Antihypertensive agents</topic><topic>Antihypertensive Agents - 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(Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Altmaier, Elisabeth</au><au>Menni, Cristina</au><au>Heier, Margit</au><au>Meisinger, Christa</au><au>Thorand, Barbara</au><au>Quell, Jan</au><au>Kobl, Michael</au><au>Römisch-Margl, Werner</au><au>Valdes, Ana M</au><au>Mangino, Massimo</au><au>Waldenberger, Melanie</au><au>Strauch, Konstantin</au><au>Illig, Thomas</au><au>Adamski, Jerzy</au><au>Spector, Tim</au><au>Gieger, Christian</au><au>Suhre, Karsten</au><au>Kastenmüller, Gabi</au><au>Casarini, Dulce Elena</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-04-27</date><risdate>2016</risdate><volume>11</volume><issue>4</issue><spage>e0153163</spage><pages>e0153163-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27120469</pmid><doi>10.1371/journal.pone.0153163</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-04, Vol.11 (4), p.e0153163 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1784751690 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | ACE protein Adult Aged Agent Orange Angiotensin-converting enzyme inhibitors Angiotensin-Converting Enzyme Inhibitors - therapeutic use Antihypertensive agents Antihypertensive Agents - therapeutic use Antihypertensives Bioinformatics Biology Biology and Life Sciences Blood Blood levels Blood pressure Blood Pressure - drug effects Blood Pressure - genetics Cardiovascular diseases Chemical industry Diabetes Dipeptides - metabolism Environmental health Enzymes Epidemiology Female Genetic diversity Genetic variance Genetic Variation - drug effects Genetic Variation - genetics Genetics Genomes Genotype Genotypes Health aspects Heterozygotes Homozygotes Humans Hypertension Hypertension - drug therapy Hypertension - genetics Hypertension - metabolism Inhibitors Loci Male Mass spectrometry Medical research Medicine and health sciences Metabolism Metabolites Metabolome - drug effects Metabolome - genetics Metabolomics Metabolomics - methods Middle Aged Narcotics Oligopeptides Oligopeptides - metabolism Peptides Peptidyl-Dipeptidase A - genetics Peptidyl-Dipeptidase A - metabolism Pharmacogenetics - methods Pharmacology Physical Sciences Physiology Polypeptides Population studies Population-based studies Research and Analysis Methods Risk factors Scientific imaging Studies Substrates |
| title | The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study |
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