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Eleven Genomic Loci Affect Plasma Levels of Chronic Inflammation Marker Soluble Urokinase-type Plasminogen Activator Receptor

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Joseph Dowsett, Egil Ferkingstad, Line Jee Hartmann Rasmussen, Lise Wegner Thørner, Magnus Karl Magnusson, Karen Sugden, Gudmar Thorleifsson, Mike Frigge, Kristoffer Solvsten Burgdorf, Sisse Rye Ostrowski, Erik Sørensen, Christian Erikstrup, Ole Birger Pedersen, Thomas Folkmann Hansen, Karina Banasik, Søren Brunak, Vinicius Tragante, Sigrun Helga Lund, Lilja Stefansdottir, Bjarni Gunnarson & 9 more Richie Poulton, Louise Arseneault, Avshalom Caspi, Terrie E. Moffitt, Daniel F. Gudbjartsson, Jesper Eugen-Olsen, Hreinn Stefansson, Kári Stefánsson, Henrik Ullum

Original languageEnglish
JournalCommunications Biology
Accepted/In press6 Apr 2021

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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.

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