TY - JOUR
T1 - Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk
AU - Olson, N. C.
AU - Raffield, L. M.
AU - Lange, L. A.
AU - Lange, E. M.
AU - Longstreth, W. T.
AU - Chauhan, G.
AU - Debette, S.
AU - Seshadri, S.
AU - Reiner, A. P.
AU - Tracy, R. P.
N1 - Funding Information:
The authors acknowledge Diagnostica Stago, Inc. for proving the FVIIa and FVIIa-AT assays. Diagnostica Stago, Inc. had an opportunity to review the manuscript but did not have any role in the design or conduct of the study, the collection, management, analysis or interpretation of the data, the preparation of the manuscript, or the decision to publish. The authors thank the staff and participants of each of the studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium for their important contributions and all members of the Neurology Working Group of the CHARGE Consortium. This study was supported by an R01 (HL71862) from the National Heart, Blood, and Lung Institute (NHLBI) to A. P. Reiner. N C. Olson was supported by the NHLBI post-doctoral training award 5T32HL007894 and NHLBI K99HL129045. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. G. Chauhan and S. Debette were supported by a grant from the Fon-dation Leducq and the Agence Nationale de la Recherche (Chaire d’Excellence). Information about the funding for cohorts included in the CHARGE Consortium is provided in the Supplementary Material.
Funding Information:
The authors acknowledge Diagnostica Stago, Inc. for proving the FVIIa and FVIIa-AT assays. Diagnostica Stago, Inc. had an opportunity to review the manuscript but did not have any role in the design or conduct of the study, the collection, management, analysis or interpretation of the data, the preparation of the manuscript, or the decision to publish. The authors thank the staff and participants of each of the studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium for their important contributions and all members of the Neurology Working Group of the CHARGE Consortium. This study was supported by an R01 (HL71862) from the National Heart, Blood, and Lung Institute (NHLBI) to A. P. Reiner. N C. Olson was supported by the NHLBI post-doctoral training award 5T32HL007894 and NHLBI K99HL129045. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. G. Chauhan and S. Debette were supported by a grant from the Fondation Leducq and the Agence Nationale de la Recherche (Chaire d'Excellence). Information about the funding for cohorts included in the CHARGE Consortium is provided in the Supplementary Material.
Publisher Copyright:
© 2017 International Society on Thrombosis and Haemostasis
PY - 2018/1
Y1 - 2018/1
N2 - Essentials: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. Summary: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = −25.9 mU mL−1 per minor allele; FVIIa-AT, β = −26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL−1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.
AB - Essentials: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. Summary: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = −25.9 mU mL−1 per minor allele; FVIIa-AT, β = −26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL−1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.
KW - antithrombin
KW - cardiovascular disease
KW - coagulation factor VII
KW - epidemiology
KW - single nucleotide polymorphisms
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U2 - 10.1111/jth.13899
DO - 10.1111/jth.13899
M3 - Article
C2 - 29112333
AN - SCOPUS:85040078821
VL - 16
SP - 19
EP - 30
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
SN - 1538-7933
IS - 1
ER -