Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease.
Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasm...
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Public Library of Science (PLoS)
2017-04-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1006706 |
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| author | Lasse Folkersen Eric Fauman Maria Sabater-Lleal Rona J Strawbridge Mattias Frånberg Bengt Sennblad Damiano Baldassarre Fabrizio Veglia Steve E Humphries Rainer Rauramaa Ulf de Faire Andries J Smit Philippe Giral Sudhir Kurl Elmo Mannarino Stefan Enroth Åsa Johansson Sofia Bosdotter Enroth Stefan Gustafsson Lars Lind Cecilia Lindgren Andrew P Morris Vilmantas Giedraitis Angela Silveira Anders Franco-Cereceda Elena Tremoli IMPROVE study group Ulf Gyllensten Erik Ingelsson Søren Brunak Per Eriksson Daniel Ziemek Anders Hamsten Anders Mälarstig |
| author_facet | Lasse Folkersen Eric Fauman Maria Sabater-Lleal Rona J Strawbridge Mattias Frånberg Bengt Sennblad Damiano Baldassarre Fabrizio Veglia Steve E Humphries Rainer Rauramaa Ulf de Faire Andries J Smit Philippe Giral Sudhir Kurl Elmo Mannarino Stefan Enroth Åsa Johansson Sofia Bosdotter Enroth Stefan Gustafsson Lars Lind Cecilia Lindgren Andrew P Morris Vilmantas Giedraitis Angela Silveira Anders Franco-Cereceda Elena Tremoli IMPROVE study group Ulf Gyllensten Erik Ingelsson Søren Brunak Per Eriksson Daniel Ziemek Anders Hamsten Anders Mälarstig |
| author_sort | Lasse Folkersen |
| collection | DOAJ |
| description | Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets. |
| format | Article |
| id | doaj-art-bc8426e00b414c1fa9c00ba7d8da1ed8 |
| institution | Matheson Library |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2017-04-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-bc8426e00b414c1fa9c00ba7d8da1ed82025-06-26T05:30:58ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-04-01134e100670610.1371/journal.pgen.1006706Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease.Lasse FolkersenEric FaumanMaria Sabater-LlealRona J StrawbridgeMattias FrånbergBengt SennbladDamiano BaldassarreFabrizio VegliaSteve E HumphriesRainer RauramaaUlf de FaireAndries J SmitPhilippe GiralSudhir KurlElmo MannarinoStefan EnrothÅsa JohanssonSofia Bosdotter EnrothStefan GustafssonLars LindCecilia LindgrenAndrew P MorrisVilmantas GiedraitisAngela SilveiraAnders Franco-CerecedaElena TremoliIMPROVE study groupUlf GyllenstenErik IngelssonSøren BrunakPer ErikssonDaniel ZiemekAnders HamstenAnders MälarstigRecent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.https://doi.org/10.1371/journal.pgen.1006706 |
| spellingShingle | Lasse Folkersen Eric Fauman Maria Sabater-Lleal Rona J Strawbridge Mattias Frånberg Bengt Sennblad Damiano Baldassarre Fabrizio Veglia Steve E Humphries Rainer Rauramaa Ulf de Faire Andries J Smit Philippe Giral Sudhir Kurl Elmo Mannarino Stefan Enroth Åsa Johansson Sofia Bosdotter Enroth Stefan Gustafsson Lars Lind Cecilia Lindgren Andrew P Morris Vilmantas Giedraitis Angela Silveira Anders Franco-Cereceda Elena Tremoli IMPROVE study group Ulf Gyllensten Erik Ingelsson Søren Brunak Per Eriksson Daniel Ziemek Anders Hamsten Anders Mälarstig Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. PLoS Genetics |
| title | Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. |
| title_full | Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. |
| title_fullStr | Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. |
| title_full_unstemmed | Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. |
| title_short | Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. |
| title_sort | mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease |
| url | https://doi.org/10.1371/journal.pgen.1006706 |
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