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Genome‐wide analysis of genetic determinants of circulating factor VII‐activating protease (FSAP) activity
Author(s): ,
M. Olsson
Affiliations:
Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Correspondence: Maja Olsson, Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Box 445, SE‐405 30 Gothenburg, Sweden|Tel.: +46 31 343 4805|E‐mail: maja.olsson@gu.se
,
T. M. Stanne
Affiliations:
Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
,
A. Pedersen
Affiliations:
Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
,
E. Lorentzen
Affiliations:
Bioinformatics Core Facility, University of Gothenburg, Gothenburg, Sweden
,
E. Kara
Affiliations:
Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
,
A. Martinez‐Palacian
Affiliations:
Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
,
N. P. Rønnow Sand
Affiliations:
Department of Cardiology, Hospital of South West Denmark, Esbjerg and Department of Regional Health Research, Faculty of Health Science, University of Southern Denmark, Esbjerg, Denmark
,
A. F. Jacobsen
Affiliations:
Department of Obstetrics, Oslo University Hospital and University of Oslo, Oslo, Norway
,
P. M. Sandset
Affiliations:
Department of Hematology, Oslo University Hospital and University of Oslo, Oslo, Norway
,
J. J. Sidelmann
Affiliations:
Unit for Thrombosis Research, Department of Regional Health Research, Faculty of Health Science, University of Southern Denmark, Esbjerg, Denmark
,
G. Engström
Affiliations:
Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
,
O. Melander
Affiliations:
Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
,
S. M. Kanse
Affiliations:
Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
C. Jern
Affiliations:
Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
ISTH Academy. Olsson M. Oct 4, 2018; 234152
Maja Olsson
Maja  Olsson

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Background
Factor VII‐activating protease (FSAP) has roles in both coagulation and fibrinolysis. Recent data indicate its involvement in several other processes, such as vascular remodeling and inflammation. Plasma FSAP activity is highly variable among healthy individuals and, apart from the low‐frequency missense variant Marburg‐I (rs7080536) in the FSAP‐encoding gene HABP2, determinants of this variation are unclear.
Objectives
To identify novel genetic variants within and outside of the HABP2 locus that influence circulating FSAP activity.
Patients/Methods
We performed an exploratory genome‐wide association study (GWAS) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with gene‐based tests. Using GWAS, we confirmed the strong association between the Marburg‐I variant and FSAP activity. HABP2 was also significant in the gene‐based analysis, and remained significant after exclusion of Marburg‐I carriers. This was attributable to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as Marburg‐I carriers, and this finding was replicated. A secondary genome‐wide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY2, which encodes a protein catalyzing the formation of cAMP.
Results and Conclusions
This study verified the Marburg‐I variant to be a strong regulator of FSAP activity, and identified an HABP2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY2 was identified as a potential additional regulator of FSAP activity.
Keyword(s)
blood coagulation factors, epidemiology, genetic variation, hemostasis, plasma
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