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Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity

Olsson, M. ; Stanne, T. M. ; Pedersen, A. ; Lorentzen, E. ; Kara, E. ; Martinez-Palacian, A. ; Rønnow Sand, N. P. ; Jacobsen, A. F. ; Sandset, P. M. and Sidelmann, J. J. , et al. (2018) In Journal of Thrombosis and Haemostasis 16(10). p.2024-2034
Abstract

Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome-wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg-1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity. Summary: 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... (More)

Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome-wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg-1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity. Summary: 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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
blood coagulation factors, epidemiology, genetic variation, hemostasis, plasma
in
Journal of Thrombosis and Haemostasis
volume
16
issue
10
pages
2024 - 2034
publisher
Wiley-Blackwell
external identifiers
  • pmid:30070759
  • scopus:85052472875
ISSN
1538-7933
DOI
10.1111/jth.14258
language
English
LU publication?
yes
id
0ea88b6a-98df-4181-b6d9-9edba44796b0
date added to LUP
2018-10-04 14:44:30
date last changed
2021-09-22 05:23:45
@article{0ea88b6a-98df-4181-b6d9-9edba44796b0,
  abstract     = {<p>Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome-wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg-1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity. Summary: 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.</p>},
  author       = {Olsson, M. and Stanne, T. M. and Pedersen, A. and Lorentzen, E. and Kara, E. and Martinez-Palacian, A. and Rønnow Sand, N. P. and Jacobsen, A. F. and Sandset, P. M. and Sidelmann, J. J. and Engström, G. and Melander, O. and Kanse, S. M. and Jern, C.},
  issn         = {1538-7933},
  language     = {eng},
  month        = {08},
  number       = {10},
  pages        = {2024--2034},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity},
  url          = {http://dx.doi.org/10.1111/jth.14258},
  doi          = {10.1111/jth.14258},
  volume       = {16},
  year         = {2018},
}