OC 17.1 - The association between venous thrombosis-associated genetic variants and coagulation factor levels and thrombin generation potential

Background: Recent three large meta-analyses of genome-wide association studies for venous thromboembolism (VTE) identified over 130 genetic variants associated with VTE. However, the mechanisms by which recently described and therefore less explored VTE-associated genetic variants increase the risk of VTE remain unclear.

Aims: We investigated the association between 61 recently described 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 were considered intermediate phenotypes for VTE.

Methods: This study was conducted on 5341 participants with European ancestry of the Netherlands Epidemiology of Obesity study. The associations between VTE-associated genetic variants and the levels of coagulation factors and thrombin generation parameters were examined using linear regression analyses, adjusting for age, sex, oral contraceptive use, hormone replacement therapy, and menopausal status. The Medical Ethical Committee of the Leiden University Medical Center, Leiden, The Netherlands approved the study. All participants gave their written informed consent.

Results: The mean (SD) age of participants was 56 (6) years and 56% were women. Of the 61 genetic variants, 19 were negatively associated with one or more of coagulation factor levels and thrombin generation parameters, of which MAP1A rs55707100 was most strongly associated with each thrombin generation parameter as well as FXI levels (-5.43 % per allele, 95% CI: -8.61, -2.26). Among the 14 genetic variants associated with increased coagulation, ST3GAL4 rs35257264 was the most strongly associated with each thrombin generation parameter as well as FVIII levels (8.30 % per allele, 95% CI: 2.29, 14.31).

Conclusion(s): These results suggest that the genetic variants likely increase the risk of VTE by affecting the coagulation pathway. Our findings contribute to a better understanding of biological mechanisms by which genetic variants increase the risk of VTE.