Human Genetic Evidence Does Not Support a Causal Role for Reduced FXI Levels in Heart Failure Pathogenesis

BACKGROUND: Coagulation FXI (factor XI) is a promising therapeutic target for preventing thromboembolic disease while preserving hemostasis. However, recent translational and epidemiological findings have raised concerns that lowering FXI levels may increase heart failure risk. To clarify these potential risks, we investigated whether lifelong genetically reduced FXI levels were associated with risk of heart failure and imaging correlates of cardiovascular function. METHODS: We used a genome-wide association study of circulating FXI levels in the deCODE cohort (n=35 559) to identify a genetic proxy in the F11 gene for circulating FXI levels. To validate this genetic proxy, we examined its associations with positive control thromboembolic diseases and its mechanistic specificity using cardiovascular risk factors unrelated to coagulation. We then obtained genetic associations for the primary outcome of all-cause heart failure (139 533 cases and 1 568 809 controls) and secondary outcomes of heart failure subtypes (up to 42 081 cases), atrial fibrillation (181 446 cases), and magnetic resonance imaging correlates of cardiovascular function (up to 38 251 participants). We performed Mendelian randomization analyses using the Wald ratio method to estimate the association of a lifelong 1-SD reduction in genetically proxied FXI levels on each outcome. RESULTS: We identified an F11 variant that reduced circulating FXI levels by 0.33 SD units ( P <1×10 −200 ), conferred protection against venous thromboembolism (odds ratio per 1-SD reduction in FXI levels, 0.61 [95% CI, 0.60–0.63]; P =1.85×10 −198 ), and showed no association with cardiovascular risk factors ( P >0.05). Genetically proxied lower FXI levels were not associated with all-cause heart failure (odds ratio, 0.99 [95% CI, 0.96–1.01]; P =0.34), nor with any secondary clinical or radiographic outcomes (all P >0.05). CONCLUSIONS: Current human genetic evidence does not support an adverse effect of lower FXI levels on heart failure risk or cardiovascular function. Further studies examining the effect of FXI levels on cardiac events and function are warranted.