Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
Blood. 2020 Dec 24;136(26):3062-3069. doi: 10.1182/blood.2019004781.
Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.
纤维蛋白原是凝血级联反应的关键组成部分，其循环水平的变化可能导致血栓性疾病，如静脉血栓栓塞症（VTE）和缺血性中风。γ'纤维蛋白原是纤维蛋白原的一种同工型，具有抗凝血特性。我们应用两样本 Mendelian 随机化（MR）方法，使用全基因组关联研究的汇总统计数据，估计总循环纤维蛋白原及其同工型γ'纤维蛋白原对 VTE 和缺血性中风亚型风险的因果效应。选择了γ'纤维蛋白原和总纤维蛋白原的遗传工具，并在主要分析中使用逆方差加权 MR 方法估计因果效应，补充了更能抵抗包含多效性变异的敏感性分析，包括 MR-Egger、加权中位数 MR 和加权模式 MR。基于 16 个γ'纤维蛋白原遗传工具和 75 个总纤维蛋白原遗传工具的综合分析，主要的逆方差加权 MR 估计表明，较高的γ'纤维蛋白原和较高的总纤维蛋白原对 VTE 风险具有保护作用。较高的γ'纤维蛋白原水平对心源性栓塞和大动脉中风风险也具有保护作用。敏感性分析的结果一致。我们的结果为遗传决定的γ'纤维蛋白原对 VTE 和缺血性中风风险的影响提供了证据。需要进一步研究以探索这些影响的机制及其临床应用。
