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

Maja Olsson, T M Stanne, A Pedersen, E Lorentzen, E Kara, A Martinez-Palacian, N P Rønnow Sand, A F Jacobsen, P M Sandset, J J Sidelmann, G Engström, O Melander, S M Kanse, C Jern

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Abstract

BACKGROUND: Factor VII activating protease (FSAP) exerts a role in both coagulation and fibrinolysis. Recent data indicate 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: We therefore sought 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 3,230 Swedish subjects. Directly genotyped rare variants were also analyzed by gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. The HABP2 gene was significant also in the gene-based analysis, and remained significant after excluding Marburg-I carriers. This was due to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant displayed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at chromosome 5p15 (rs35510613), and this finding requires future replication. This common variant is located upstream of the ADCY2 gene, 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 a HABP2 stop variant with a similar impact on FSAP activity. A novel locus near the ADCY2 gene was identified as a potential additional regulator of FSAP activity. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalJournal of Thrombosis and Haemostasis
Volume16
Issue number10
Pages (from-to)2024-2034
ISSN1538-7933
DOIs
Publication statusPublished - 2018

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Peptide Hydrolases
Genome-Wide Association Study
Fibrinolysis
Proteins

Keywords

  • blood coagulation factors
  • epidemiology
  • genetic variation
  • hemostasis
  • plasma

Cite this

Olsson, M., Stanne, T. M., Pedersen, A., Lorentzen, E., Kara, E., Martinez-Palacian, A., ... Jern, C. (2018). Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity. Journal of Thrombosis and Haemostasis, 16(10), 2024-2034. https://doi.org/10.1111/jth.14258
Olsson, Maja ; Stanne, T M ; Pedersen, A ; Lorentzen, E ; Kara, E ; Martinez-Palacian, A ; Rønnow Sand, N P ; Jacobsen, A F ; Sandset, P M ; Sidelmann, J J ; Engström, G ; Melander, O ; Kanse, S M ; Jern, C. / Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity. In: Journal of Thrombosis and Haemostasis. 2018 ; Vol. 16, No. 10. pp. 2024-2034.
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abstract = "BACKGROUND: Factor VII activating protease (FSAP) exerts a role in both coagulation and fibrinolysis. Recent data indicate 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: We therefore sought 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 3,230 Swedish subjects. Directly genotyped rare variants were also analyzed by gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. The HABP2 gene was significant also in the gene-based analysis, and remained significant after excluding Marburg-I carriers. This was due to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant displayed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at chromosome 5p15 (rs35510613), and this finding requires future replication. This common variant is located upstream of the ADCY2 gene, 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 a HABP2 stop variant with a similar impact on FSAP activity. A novel locus near the ADCY2 gene was identified as a potential additional regulator of FSAP activity. This article is protected by copyright. All rights reserved.",
keywords = "blood coagulation factors, epidemiology, genetic variation, hemostasis, plasma",
author = "Maja Olsson and Stanne, {T M} and A Pedersen and E Lorentzen and E Kara and A Martinez-Palacian and {R{\o}nnow Sand}, {N P} and Jacobsen, {A F} and Sandset, {P M} and Sidelmann, {J J} and G Engstr{\"o}m and O Melander and Kanse, {S M} and C Jern",
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year = "2018",
doi = "10.1111/jth.14258",
language = "English",
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Olsson, M, Stanne, TM, Pedersen, A, Lorentzen, E, Kara, E, Martinez-Palacian, A, Rønnow Sand, NP, Jacobsen, AF, Sandset, PM, Sidelmann, JJ, Engström, G, Melander, O, Kanse, SM & Jern, C 2018, 'Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity', Journal of Thrombosis and Haemostasis, vol. 16, no. 10, pp. 2024-2034. https://doi.org/10.1111/jth.14258

Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity. / Olsson, Maja; Stanne, T M; Pedersen, A; Lorentzen, E; Kara, E; Martinez-Palacian, A; Rønnow Sand, N P; Jacobsen, A F; Sandset, P M; Sidelmann, J J; Engström, G; Melander, O; Kanse, S M; Jern, C.

In: Journal of Thrombosis and Haemostasis, Vol. 16, No. 10, 2018, p. 2024-2034.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity

AU - Olsson, Maja

AU - Stanne, T M

AU - Pedersen, A

AU - Lorentzen, E

AU - Kara, E

AU - Martinez-Palacian, A

AU - Rønnow Sand, N P

AU - Jacobsen, A F

AU - Sandset, P M

AU - Sidelmann, J J

AU - Engström, G

AU - Melander, O

AU - Kanse, S M

AU - Jern, C

N1 - This article is protected by copyright. All rights reserved.

PY - 2018

Y1 - 2018

N2 - BACKGROUND: Factor VII activating protease (FSAP) exerts a role in both coagulation and fibrinolysis. Recent data indicate 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: We therefore sought 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 3,230 Swedish subjects. Directly genotyped rare variants were also analyzed by gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. The HABP2 gene was significant also in the gene-based analysis, and remained significant after excluding Marburg-I carriers. This was due to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant displayed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at chromosome 5p15 (rs35510613), and this finding requires future replication. This common variant is located upstream of the ADCY2 gene, 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 a HABP2 stop variant with a similar impact on FSAP activity. A novel locus near the ADCY2 gene was identified as a potential additional regulator of FSAP activity. This article is protected by copyright. All rights reserved.

AB - BACKGROUND: Factor VII activating protease (FSAP) exerts a role in both coagulation and fibrinolysis. Recent data indicate 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: We therefore sought 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 3,230 Swedish subjects. Directly genotyped rare variants were also analyzed by gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. The HABP2 gene was significant also in the gene-based analysis, and remained significant after excluding Marburg-I carriers. This was due to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant displayed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at chromosome 5p15 (rs35510613), and this finding requires future replication. This common variant is located upstream of the ADCY2 gene, 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 a HABP2 stop variant with a similar impact on FSAP activity. A novel locus near the ADCY2 gene was identified as a potential additional regulator of FSAP activity. This article is protected by copyright. All rights reserved.

KW - blood coagulation factors

KW - epidemiology

KW - genetic variation

KW - hemostasis

KW - plasma

U2 - 10.1111/jth.14258

DO - 10.1111/jth.14258

M3 - Journal article

C2 - 30070759

VL - 16

SP - 2024

EP - 2034

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 10

ER -