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Associations of activated coagulation factor VII and factor VII a‐antithrombin levels with genome‐wide polymorphisms and cardiovascular disease risk
Author(s) -
Olson N. C.,
Raffield L. M.,
Lange L. A.,
Lange E. M.,
Longstreth W. T.,
Chauhan G.,
Debette S.,
Seshadri S.,
Reiner A. P.,
Tracy R. P.
Publication year - 2018
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13899
Subject(s) - medicine , minor allele frequency , single nucleotide polymorphism , antithrombin , coagulation , risk factor , gastroenterology , genetics , genotype , biology , heparin , gene
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 ( FVII a). FVII a also circulates as an inactivated complex with antithrombin ( FVII a‐ AT ). Objective Evaluate associations of FVII a and FVII a‐ AT with genome‐wide single nucleotide polymorphisms ( SNP s) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVII a and FVII a‐ AT in 3486 Cardiovascular Health Study ( CHS ) participants. We performed a genome‐wide association scan for FVII a and FVII a‐ 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 FVII a and FVII a‐ AT was rs1755685 in the F7 promoter region on chromosome 13 ( FVII a, β = −25.9 mU mL −1 per minor allele; FVII a‐ AT , β = −26.6 p m per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 ( FVII a, β = 7.8 mU mL −1 per minor allele; FVII a‐ AT , β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVII a was associated with increased risk of ischemic stroke (hazard ratio [ HR ], 1.12; 95% confidence interval [ CI ], 1.01, 1.23). Higher FVII a‐ 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 FVII a and FVII a‐ AT . The findings suggest FVII a is a risk factor for ischemic stroke in older adults, whereas higher FVII a‐ AT may reflect mortality risk.