Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor

Dowsett, Joseph; Ferkingstad, Egil; Rasmussen, Line Jee Hartmann; Thørner, Lise Wegner; Magnússon, Magnús Karl; Sugden, Karen; Þorleifsson, Guðmar; Frigge, Mike; Burgdorf, Kristoffer Sølvsten; Ostrowski, Sisse Rye; Sørensen, Erik; Erikstrup, Christian; Pedersen, Ole Birger; Hansen, Thomas Folkmann; Banasik, Karina; Brunak, Søren; Tragante, Vinicius; Lund, Sigrún Helga; Stefánsdóttir, Lilja; Gunnarson, Bjarni; Poulton, Richie; Arseneault, Louise; Caspi, Avshalom; Moffitt, Terrie E.; Gudbjartsson, Daníel Fannar; Eugen-Olsen, Jesper; Stefánsson, Hreinn; Stefánsson, Kári; Ullum, Henrik

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Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor

Title:	Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor
Author:	Dowsett, Joseph Ferkingstad, Egil orcid.org/0000-0001-8090-7988 Rasmussen, Line Jee Hartmann Thørner, Lise Wegner Magnússon, Magnús Karl Sugden, Karen Þorleifsson, Guðmar Frigge, Mike Burgdorf, Kristoffer Sølvsten Ostrowski, Sisse Rye ... 19 more authors Show all authors Sørensen, Erik Erikstrup, Christian Pedersen, Ole Birger Hansen, Thomas Folkmann Banasik, Karina Brunak, Søren Tragante, Vinicius Lund, Sigrún Helga orcid.org/0000-0002-3806-2296 Stefánsdóttir, Lilja Gunnarson, Bjarni Poulton, Richie Arseneault, Louise Caspi, Avshalom Moffitt, Terrie E. Gudbjartsson, Daníel Fannar Eugen-Olsen, Jesper Stefánsson, Hreinn Stefánsson, Kári Ullum, Henrik 29 authors Show fewer authors
Date:	2021-06-02
Language:	English
Scope:	1
University/Institute:	Landspitali - The National University Hospital of Iceland
Department:	Faculty of Medicine Faculty of Physical Sciences
Series:	Communications Biology; 4(1)
ISSN:	2399-3642
DOI:	10.1038/s42003-021-02144-8
Subject:	Bólgur; Erfðafræði; Lífmerki; Lífmerki; Litningar; Biomarkers; Chromosome mapping; Inflammation mediators; Multifactoral inheritance; Genome-wide association study; polymorphism, single nucleotide; Quantitative trait; Heritable; Receptors; Urokinase Plasminogen Activator; Cohort studies; C-Reactive Protein; General Agricultural and Biological Sciences; General Biochemistry,Genetics and Molecular Biology; Medicine (miscellaneous)
URI:	https://hdl.handle.net/20.500.11815/3123
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Citation: Dowsett , J , Ferkingstad , E , Rasmussen , L J H , Thørner , L W , Magnússon , M K , Sugden , K , Þorleifsson , G , Frigge , M , Burgdorf , K S , Ostrowski , S R , Sørensen , E , Erikstrup , C , Pedersen , O B , Hansen , T F , Banasik , K , Brunak , S , Tragante , V , Lund , S H , Stefánsdóttir , L , Gunnarson , B , Poulton , R , Arseneault , L , Caspi , A , Moffitt , T E , Gudbjartsson , D F , Eugen-Olsen , J , Stefánsson , H , Stefánsson , K & Ullum , H 2021 , ' Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor ' , Communications Biology , vol. 4 , no. 1 , pp. 655 . https://doi.org/10.1038/s42003-021-02144-8
Abstract: Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR's potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation.
Description: This study was supported by the Danish Council for Independent Research (09-069412 and 0602-02634B), Aase og Ejnar Danielsens Fond, AP Møller Fonden, and the Danish Regions (02/2611). The DBDS genetic infrastructure was supported by the Novo Nordic Foundation (NNF17OC0027594). S.B. reports grants from Innovation Fund Denmark, grants from Novo Nordisk Foundation during the conduct of the study; and personal fees from Intomics A/S and Proscion A/S, outside the submitted work. S.B. and K.B. report on behalf of Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, that the following grants supported the study: The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594) and The Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115881 (RHAPSODY). L.J.H.R. is supported by an international postdoctoral fellowship from the Lundbeck Foundation (grant no. R288-2018-380). The E-Risk Study is funded by the Medical Research Council (UKMRC grant G1002190). Additional support was provided by the National Institute of Child Health and Human Development (grant HD077482) and by the Jacobs Foundation. The authors are grateful to the Study members and their families for their participation. Our thanks CACI, Inc., and to members of the E-Risk team for their dedication, hard work, and insights. We thank the Dunedin Study members, Unit research staff, and Study founder Phil Silva. This research was supported by US-National Institute on Aging grants AG032282 and UK Medical Research Council grant MR/P005918/1. The Dunedin Multidisciplinary Health and Development Research Unit is supported by the New Zealand Health Research Council Programme Grant (16-604), and the New Zealand Ministry of Business, Innovation, and Employment (MBIE).