Han Jihee, Li-Gao Ruifang, de Mutsert Renée, Rosendaal Frits R, van Hylckama Vlieg Astrid
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands.
EJHaem. 2024 Feb 18;5(1):47-54. doi: 10.1002/jha2.863. eCollection 2024 Feb.
Recently three large meta-analyses of genome-wide association studies for venous thromboembolism (VTE) identified over 130 genetic variants. However, mechanisms by which newly identified and therefore underexplored VTE-associated genetic variants influence VTE remain unclear. To elucidate the mechanism, we investigated the association between 61 newly identified VTE-associated genetic variants and the levels of coagulation factor (F) VIII, FIX, FXI, and fibrinogen as well as thrombin generation parameters (lag time, peak, endogenous thrombin potential, time-to-peak, and velocity), which are well-known biological traits associated with VTE. This study was conducted on 5341 participants of the Netherlands Epidemiology of Obesity study. The associations between VTE-associated genetic variants and coagulation factor levels and thrombin generation parameters were examined using linear regression analyses, adjusted for age, sex, body mass index, oral contraceptive use, hormone replacement therapy, and menopausal status. Of 61 genetic variants, 33 were associated with one or more of the coagulation factor levels and thrombin generation parameters. Following multiple testing corrections, five genetic variants remained significant, of which rs55707100 exhibited the most robust association with thrombin generation parameters and FXI levels (β = -5.33%, 95% confidence interval: -8.44, -2.22). Our findings shed light on the underlying mechanisms by which these genetic variants influence the risk of VTE.
最近，三项针对静脉血栓栓塞症（VTE）的全基因组关联研究的大型荟萃分析确定了130多个基因变异。然而，新发现的、因此尚未充分研究的VTE相关基因变异影响VTE的机制仍不清楚。为了阐明该机制，我们研究了61个新发现的VTE相关基因变异与凝血因子（F）VIII、FIX、FXI和纤维蛋白原水平以及凝血酶生成参数（滞后时间、峰值、内源性凝血酶潜力、达到峰值的时间和速度）之间的关联，这些都是与VTE相关的众所周知的生物学特征。这项研究是在5341名荷兰肥胖流行病学研究参与者中进行的。使用线性回归分析检查VTE相关基因变异与凝血因子水平和凝血酶生成参数之间的关联，并对年龄、性别、体重指数、口服避孕药使用、激素替代疗法和绝经状态进行了调整。在61个基因变异中，33个与一种或多种凝血因子水平和凝血酶生成参数相关。经过多次检验校正后，五个基因变异仍然显著，其中rs55707100与凝血酶生成参数和FXI水平表现出最强的关联（β = -5.33%，95%置信区间：-8.44，-2.22）。我们的研究结果揭示了这些基因变异影响VTE风险的潜在机制。
