title: Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease.
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.
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Copenhagen, Denmark.|Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lasse
authors.identifier: http://orcid.org/0000-0003-0708-9530
authors.initials: L
authors.lastname: Folkersen
authors.affiliation: Pfizer Worldwide Research & Development, Cambridge, Massachusetts, United States of America.
authors.forename: Eric
authors.identifier: http://orcid.org/0000-0002-9739-0249
authors.initials: E
authors.lastname: Fauman
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0002-0128-379X
authors.initials: M
authors.lastname: Sabater-Lleal
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Frånberg
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Sennblad
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.|Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Damiano
authors.identifier: http://orcid.org/0000-0002-2766-8882
authors.initials: D
authors.lastname: Baldassarre
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.affiliation: British Heart Foundation Laboratories, University College of London, Department of Medicine, Rayne Building, London, United Kingdom.
authors.forename: Steve E
authors.identifier: http://orcid.org/0000-0002-8221-6547
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Rauramaa
authors.affiliation: Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.affiliation: Department of Medicine, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Andries J
authors.initials: AJ
authors.lastname: Smit
authors.affiliation: Assistance Publique - Hopitaux de Paris; Service Endocrinologie-Metabolisme, Groupe Hôpitalier Pitie-Salpetriere, Unités de Prévention Cardiovasculaire, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Giral
authors.affiliation: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kurl
authors.affiliation: Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Elmo
authors.initials: E
authors.lastname: Mannarino
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.identifier: http://orcid.org/0000-0002-5056-9137
authors.initials: S
authors.lastname: Enroth
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Åsa
authors.identifier: http://orcid.org/0000-0002-2915-4498
authors.initials: Å
authors.lastname: Johansson
authors.affiliation: Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Sofia Bosdotter
authors.initials: SB
authors.lastname: Enroth
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lindgren
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Vilmantas
authors.initials: V
authors.lastname: Giedraitis
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.affiliation: Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.|Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.identifier: http://orcid.org/0000-0002-5635-2692
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Pfizer Worldwide Research & Development, Cambridge, Massachusetts, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Pfizer Worldwide Research and Development, Stockholm, Sweden.
authors.forename: Anders
authors.identifier: http://orcid.org/0000-0003-2608-1358
authors.initials: A
authors.lastname: Mälarstig
mesh_terms: D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics*; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D040641:Quantitative Trait Loci
chemical_list: D015415:Biomarkers; D001798:Blood Proteins