Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.
BACKGROUND
The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts.


OBJECTIVE
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.


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.
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.
N C
NC
Olson
Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT, USA.
S
S
Butenas
Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
L A
LA
Lange
Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.|Department of Biostatistics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
E M
EM
Lange
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.|Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA.
M
M
Cushman
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.
N S
NS
Jenny
Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J
J
Walston
Department of Hematology, Institute of Biomedical Research (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
J C
JC
Souto
Unit of Genomics of Complex Diseases, Institute of Biomedical Research (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
J M
JM
Soria
INSERM U897, University of Bordeaux, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
G
G
Chauhan
INSERM U897, University of Bordeaux, Bordeaux, France.|University of Bordeaux, Bordeaux, France.|Bordeaux University Hospital, Bordeaux, France.|Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
S
S
Debette
Department of Neurology, University of Washington, Seattle, WA, USA.|Department of Epidemiology, University of Washington, Seattle, WA, USA.
W T
WT
Longstreth
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
S
S
Seshadri
Department of Epidemiology, University of Washington, Seattle, WA, USA.
A P
AP
Reiner
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.|Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT, USA.
R P
RP
Tracy
D001741:Black or African American / Q000235:genetics; D000367:Age Factors; D000368:Aged; D001777:Blood Coagulation / Q000235:genetics*; D002545:Brain Ischemia / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D005174:Factor XII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D013917:Thrombin / Q000378:metabolism*; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
D005174:Factor XII; D013917:Thrombin
cardiovascular diseases; epidemiology; factor XIIa; single nucleotide polymorphisms; thrombin