Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease

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 M Lindgren; Andrew P Morris; Vilmantas Giedraitis; Angela Silveira; Anders Franco-Cereceda; Elena Tremoli; Ulf Gyllensten; Erik Ingelsson; Søren Brunak; Per Eriksson; Daniel Ziemek; Anders Hamsten; Anders Mälarstig

doi:10.1371/journal.pgen.1006706

Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease

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 LindCecilia M Lindgren, Andrew P Morris, Vilmantas Giedraitis, Angela Silveira, Anders Franco-Cereceda, Elena Tremoli, Ulf Gyllensten, Erik Ingelsson, Søren Brunak, Per Eriksson, Daniel Ziemek, Anders Hamsten, Anders Mälarstig

53 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	e1006706
Tidsskrift	P L o S Genetics
Vol/bind	13
Udgave nummer	4
Antal sider	21
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1006706
Status	Udgivet - apr. 2017
Udgivet eksternt	Ja

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10.1371/journal.pgen.1006706

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Folkersen, L., Fauman, E., Sabater-Lleal, M., Strawbridge, R. J., Frånberg, M., Sennblad, B., Baldassarre, D., Veglia, F., Humphries, S. E., Rauramaa, R., de Faire, U., Smit, A. J., Giral, P., Kurl, S., Mannarino, E., Enroth, S., Johansson, Å., Enroth, S. B., Gustafsson, S., ... Mälarstig, A. (2017). Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. P L o S Genetics, 13(4), [e1006706]. https://doi.org/10.1371/journal.pgen.1006706

Folkersen, L, Fauman, E, Sabater-Lleal, M, Strawbridge, RJ, Frånberg, M, Sennblad, B, Baldassarre, D, Veglia, F, Humphries, SE, Rauramaa, R, de Faire, U, Smit, AJ, Giral, P, Kurl, S, Mannarino, E, Enroth, S, Johansson, Å, Enroth, SB, Gustafsson, S, Lind, L, Lindgren, CM, Morris, AP, Giedraitis, V, Silveira, A, Franco-Cereceda, A, Tremoli, E, Gyllensten, U, Ingelsson, E, Brunak, S, Eriksson, P, Ziemek, D, Hamsten, A & Mälarstig, A 2017, 'Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease', P L o S Genetics, bind 13, nr. 4, e1006706. https://doi.org/10.1371/journal.pgen.1006706

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abstract = "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.",

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T1 - Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease

AU - Folkersen, Lasse

AU - Fauman, Eric

AU - Sabater-Lleal, Maria

AU - Strawbridge, Rona J

AU - Frånberg, Mattias

AU - Sennblad, Bengt

AU - Baldassarre, Damiano

AU - Veglia, Fabrizio

AU - Humphries, Steve E

AU - Rauramaa, Rainer

AU - de Faire, Ulf

AU - Smit, Andries J

AU - Giral, Philippe

AU - Kurl, Sudhir

AU - Mannarino, Elmo

AU - Enroth, Stefan

AU - Johansson, Åsa

AU - Enroth, Sofia Bosdotter

AU - Gustafsson, Stefan

AU - Lind, Lars

AU - Lindgren, Cecilia M

AU - Morris, Andrew P

AU - Giedraitis, Vilmantas

AU - Silveira, Angela

AU - Franco-Cereceda, Anders

AU - Tremoli, Elena

AU - Gyllensten, Ulf

AU - Ingelsson, Erik

AU - Brunak, Søren

AU - Eriksson, Per

AU - Ziemek, Daniel

AU - Hamsten, Anders

AU - Mälarstig, Anders

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1371/journal.pgen.1006706

DO - 10.1371/journal.pgen.1006706

M3 - Journal article

C2 - 28369058

SN - 1553-7390

VL - 13

JO - P L o S Genetics

JF - P L o S Genetics

IS - 4

M1 - e1006706

ER -

Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease

Abstract

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