Polygenic predisposition to venous thromboembolism is associated with increased COVID-19 positive testing rates

Genetic predisposition to venous thrombosis may impact COVID-19 infection and its sequelae. Participants in the ongoing prospective cohort study, Million Veteran Program (MVP), who were tested for COVID-19, with European ancestry, were evaluated for associations with polygenic venous thromboembolic risk, Factor V Leiden mutation (FVL) (rs6025) and prothrombin gene 3 -UTR mutation (F2 G20210A)(rs1799963), and their interactions. Logistic regression models assessed genetic associations with VTE diagnosis, COVID-19 (positive) testing rates and outcome severity (modified WHO criteria), and post-test conditions, adjusting for outpatient anticoagulation medication usage, age, sex, and genetic principal components. 108,437 out of 464,961 European American MVP participants were tested for COVID-19 with 9786 (9%) positive. PRS(VTE), FVL, F2 G20210A were not significantly associated with the propensity of being tested for COVID-19. PRS(VTE) was significantly associated with a positive COVID-19 test in F5 wild type (WT) individuals (OR 1.05; 95% CI [1.02-1.07]), but not in FVL carriers (0.97, [0.91-1.94]). There was no association with severe outcome for FVL, F2 G20210A or PRS(VTE). Outpatient anticoagulation usage in the two years prior to testing was associated with worse clinical outcomes. PRS(VTE) was associated with prevalent VTE diagnosis among both FVL carriers or F5 wild type individuals as well as incident VTE in the two years prior to testing. Increased genetic propensity for VTE in the MVP was associated with increased COVID-19 positive testing rates, suggesting a role of coagulation in the initial steps of COVID-19 infection. Key PointsO_LIIncreased genetic predisposition to venous thrombosis is associated with increased COVID-19 positive testing rates. C_LIO_LIPRS for VTE further risk stratifies factor V Leiden carriers regarding their VTE risk. C_LI