Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study. (14th September 2015)

• Record Type: Journal Article
• Authors: Olson, N. C.; Butenas, S.; Lange, L. A.; Lange, E. M.; Cushman, M.; Jenny, N. S.; Walston, J.; Souto, J. C.; Soria, J. M.; Chauhan, G.; Debette, S.; Longstreth, W. T.; Seshadri, S.; Reiner, A. P.; Tracy, R. P.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 13:Number 10(2015:Oct.)
• Page Start: 1867
• Page End: 1877
• Publication Date: 2015-09-14
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.13111
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth13111-abs-0001"> <title>Summary</title> <sec id="jth13111-sec-0001" sec-type="section"> <title>Background</title> <p>The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population‐based cohorts.</p> </sec> <sec id="jth13111-sec-0002" sec-type="section"> <title>Objectives</title> <p>To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways <italic>ex vivo</italic> with common single‐nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke.</p> </sec> <sec id="jth13111-sec-0003" sec-type="section"> <title>Patients/Methods</title> <p>We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (<italic>n </italic>=<italic> </italic>5411), both with and without inhibitory anti‐factor XIa antibody (pTG/FXIa<sup>−</sup>). 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.</p> </sec> <sec id="jth13111-sec-0004" sec-type="section"> <title>Results</title> <p>The minor allele for an SNP in the FXII gene (<italic>F12</italic>), rs1801020, was associated with lower pTG in European‐Americans (<italic>β</italic> = − 34.2<sc> </sc>± 3.5 n<sc>m</sc>;<italic> P </italic>=<italic> </italic>3.3 × 10<sup>−22</sup>; minor allele frequency [MAF] = 0.23) and African‐Americans (<italic>β</italic> = − 31.1 ± 7.9 n<sc>m</sc>;<italic> P </italic>=<italic> </italic>9.0 × 10<sup>−5</sup>; MAF = 0.42). Lower FXIa‐independent pTG (pTG/FXIa<sup>–</sup>) was associated with the <italic>F12</italic> rs1801020 minor allele, and higher pTG/FXIa<sup>–</sup> was associated with the <italic>ABO</italic> SNP rs657152 minor allele (<italic>β</italic> = 16.3 n<sc>m</sc>;<italic> P </italic>=<italic> </italic>4.3 × 10<sup>−9</sup>; MAF = 0.37). The risk factor‐adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI 1.01–1.17; <italic>P </italic>=<italic> </italic>0.03) for pTG, 1.06 (95% CI 0.98–1.15; <italic>P </italic>=<italic> </italic>0.17) for pTG/FXIa<sup>–</sup>, and 1.11 (95% CI 1.02–1.21; <italic>P </italic>=<italic> </italic>0.02) for FXIa‐dependent pTG (pTG/FXIa<sup>+</sup>), per one standard deviation increment (<italic>n </italic>=<italic> </italic>834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (<italic>β</italic> = − 0.02; standard error = 0.08; <italic>P</italic> = 0.81).</p> </sec> <sec id="jth13111-sec-0005" sec-type="section"> <title>Conclusions</title> <p>These results support the importance of contact activation pathway‐dependent TG as a risk factor for ischemic stroke, and indicate the importance of <italic>F12 </italic>SNPs for TG <italic>ex vivo</italic> and <italic>in vivo</italic>.</p> </sec> </abstract>