Unit of Cardiovascular and Nutritional Epidemiology Institute of Environmental MedicineKarolinska Institutet Stockholm Sweden.
Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom.
J Am Heart Assoc. 2021 Apr 20;10(8):e019644. doi: 10.1161/JAHA.120.019644. Epub 2021 Apr 9.
Background We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases. Methods and Results Genetic instruments proxying coagulation factor inhibition were identified from genome-wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age- and sex-adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large-artery stroke risk (=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage. Conclusions This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.
背景 我们进行了孟德尔随机化分析，研究了不同凝血因子的遗传近缘物抑制与常见心血管疾病风险之间的线性关联。
方法和结果 从日本生物银行（BioBank Japan）的全基因组关联研究中确定了凝血因子抑制的遗传工具，这些研究涉及活化部分凝血活酶时间和凝血酶原时间（多达 58110 名参与者）。确定了 9 种凝血因子（纤维蛋白原 alpha、beta 和 gamma 链；因子 II、V、VII、X、XI 和 XII）的遗传工具。从英国生物样本库（UK Biobank）、芬兰基因研究（FinnGen）、心血管疾病全基因组复制和荟萃分析（CardioGRAMplusC4D）和 MEGASTROKE 联盟获得了年龄和性别调整后，与结果相关的工具的估计值，其事件和现有病例数分别为 820 至 60810 例。纤维蛋白原 alpha、beta 和 gamma 链、因子 II 和因子 XI 的遗传近缘物抑制与静脉血栓栓塞风险降低相关（<0.001）。除纤维蛋白原 beta 和因子 II 外，这些因子的抑制也与任何缺血性卒中和心源性栓塞性卒中的风险降低相关（≤0.002）。纤维蛋白原 beta 和 gamma 的遗传近缘物抑制与大动脉卒中的风险降低相关（=0.001）。遗传近缘物抑制因子 V、VII 和 X 与缺血性卒中的保护关联具有提示性（<0.05），遗传近缘物抑制因子 II 和 XII 与蛛网膜下腔出血的不良关联具有提示性。
结论 本研究支持针对纤维蛋白原和因子 XI 降低静脉血栓栓塞和缺血性卒中风险，并显示出抑制因子 V、VII 和 X 可能降低缺血性卒中风险的提示性证据。
