Leveraging genetic predictors of factor XI levels to anticipate results from clinical trials

Background: Factor XI (FXI) is a promising therapeutic target for the prevention of thrombotic disease without increasing bleeding risk.Methods: We performed Mendelian randomization (MR) analyses to investigate the association of genetically predicted reductions in FXI levels with risk of venous thromboembolism, ischemic stroke, bleeding outcomes, and lifespan.Results: Genetically predicted reductions in FXI levels were associated with lower risk of ischemic stroke (odds ratio per 1 standard deviation (SD) lower serum FXI 0.90, 95% confidence interval 0.87-0.93, p = 1.59 x 10(-11)), and venous thromboembolism (0.54, 0.49-0.59, p = 2.13 x 10(-39)) but did not associate with increased bleeding risk (p > 0.16). Genetically predicted reductions in serum FXI levels associated with longer lifespan (0.37 years per 1 SD lower serum FXI, 0.13-0.61, p = 0.003).Conclusions: These genetic data support FXI as a potentially efficacious and safe therapeutic target and anticipate positive results from ongoing phase 3 clinical trials.