Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.

Abstract

BACKGROUND:

The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts.

OBJECTIVES:

To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke.

PATIENTS/METHODS:

We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n = 5411), both with and without inhibitory anti-factor XIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~ 50 000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2 years.

RESULTS:

The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β = - 34.2 ± 3.5 nm; P = 3.3 × 10(-22) ; minor allele frequency [MAF] = 0.23) and African-Americans (β = - 31.1 ± 7.9 nm; P = 9.0 × 10(-5) ; MAF = 0.42). Lower FXIa-independent pTG (pTG/FXIa(-) ) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa(-) was associated with the ABO SNP rs657152 minor allele (β = 16.3 nm; P = 4.3 × 10(-9) ; MAF = 0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI 1.01-1.17; P = 0.03) for pTG, 1.06 (95% CI 0.98-1.15; P = 0.17) for pTG/FXIa(-) , and 1.11 (95% CI 1.02-1.21; P = 0.02) for FXIa-dependent pTG (pTG/FXIa(+) ), per one standard deviation increment (n = 834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β = - 0.02; standard error = 0.08; P = 0.81).

CONCLUSIONS:

These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex vivo and in vivo.

• Authors: N C Olson, S Butenas, L A Lange, E M Lange, M Cushman, N S Jenny, J Walston, J C Souto, J M Soria, G Chauhan, S Debette, W T Longstreth, S Seshadri, A P Reiner, R P Tracy
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 13 Issue 10 Pg. 1867-77 (Oct 2015) ISSN: 1538-7836 [Electronic] England
• PMID: 26286125 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 International Society on Thrombosis and Haemostasis.

Chemical References

• Factor XII
• Thrombin

Topics

• Black or African American (genetics)
• Age Factors
• Aged
• Blood Coagulation (genetics)
• Brain Ischemia (blood, ethnology, genetics)
• Factor XII (genetics, metabolism)
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Humans
• Incidence
• Male
• Phenotype
• Polymorphism, Single Nucleotide
• Prospective Studies
• Risk Assessment
• Risk Factors
• Stroke (blood, ethnology, genetics)
• Thrombin (metabolism)
• Time Factors
• United States (epidemiology)
• White People (genetics)