Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
Cardiovascular Research Institute of Vermont, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
J Thromb Haemost. 2018 Jan;16(1):19-30. doi: 10.1111/jth.13899. Epub 2017 Dec 8.
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.
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, β = -25.9 mU mL per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL per minor allele; FVIIa-AT, β = 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 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 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.
凝血因子 VII（FVII）的一部分以活性蛋白酶（FVIIa）的形式在血液中循环。FVIIa 也以与抗凝血酶（FVIIa-AT）结合的无活性复合物的形式循环。目的：评估 FVIIa 和 FVIIa-AT 与全基因组单核苷酸多态性（SNP）及冠心病、缺血性卒中和死亡率的相关性。患者/方法：我们在 3486 名心血管健康研究（CHS）参与者中测量了 FVIIa 和 FVIIa-AT。我们对欧洲裔美国人（n=2410）进行了全基因组关联扫描，以研究 FVII 表型与心血管疾病的相关性。结果：在欧洲裔美国人中，F7 启动子区域的 rs1755685 是 FVIIa 和 FVIIa-AT 的最显著 SNP（FVIIa，β=-25.9mU·mL 每 minor allele；FVIIa-AT，β=-26.6pm 每 minor allele）。表型也与位于染色体 20 上 PROCR 区域的 rs867186 相关（FVIIa，β=7.8mU·mL 每 minor allele；FVIIa-AT，β=9.9pm 每 minor allele）。在调整了危险因素后，FVIIa 标准偏差每增加一个单位，缺血性卒中的风险增加（危险比 [HR]，1.12；95%置信区间 [CI]，1.01，1.23）。FVIIa-AT 水平较高与全因死亡率相关（HR，1.08；95%CI，1.03，1.12）。在欧洲裔美国心血管健康研究参与者中，rs1755685 等位基因与较低的缺血性卒中相关（HR，0.69；95%CI，0.54，0.88），但在一项更大的多队列分析中并未得到复制。结论：结果支持 F7 和 PROCR 基因座在循环 FVIIa 和 FVIIa-AT 变异中的重要性。研究结果表明，FVIIa 是老年人缺血性卒中的一个危险因素，而较高的 FVIIa-AT 可能反映了死亡率的风险。
