Association between venous thromboembolism-associated genetic variants, coagulation factor levels, and thrombin generation potential

Abstract

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 MAP1A 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.

Keywords: genetic variant; procoagulant factor; the Netherlands epidemiology of obesity study; thrombin generation potential; venous thromboembolism.

FIGURE 1

Flow chart of the study. ETP, endogenous thrombin potential; F, coagulation factor; HRT, hormone replacement therapy; OC, oral contraceptive; TGA, thrombin generation assay.