Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk

Olson, NC and Raffield, LM and Lange, LA and Lange, EM and Longstreth, WT and Chauhan, G and Debette, S and Seshadri, S and Reiner, AP and Tracy, RP (2018) Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk. In: JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 16 (1). pp. 19-30.

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Abstract

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, beta = -25.9 mU mL(-1) per minor allele; FVIIa-AT, beta = -26.6 pM per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, beta = 7.8 mU mL(-1) per minor allele; FVIIa-AT, beta = 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 EuropeanAmerican 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.

Item Type:	Journal Article
Publication:	JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Publisher:	10.1111/jth.13899
Additional Information:	Copy right for this article belongs to the WILEY, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Department/Centre:	Autonomous Societies / Centres > Centre for Brain Research
Date Deposited:	25 Jan 2018 06:00
Last Modified:	30 Oct 2018 05:51
URI:	http://eprints.iisc.ac.in/id/eprint/58863

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