Genetic Risk and Incident Venous Thromboembolism in Middle-aged and Older Adults Following COVID-19 Vaccination

Background: Covid-19 vaccination has been associated with the increased risk of venous thromboembolism (VTE). However, it is unknown whether genetic predisposition to VTE is associated with an increased risk of thrombosis following vaccination.

Objectives: To quantify the association between the polygenic risk score for VTE and short-term VTE occurrence following COVID-19 vaccinations.

Methods: Based on the UK Biobank, which contains in-depth genotyping data and linked vaccination and health outcomes information, we generated a polygenic risk score (PRS) using 299 genetic variants identified from a previous large genome-wide association study. We prospectively assessed associations between the PRS and incident VTE after the first and the second vaccination separately. We conducted sensitivity analyses stratified by vaccine type (adenovirus- and mRNA-based) and using two historical unvaccinated cohorts. We compared the strength of PRS-VTE associations using hazard ratios derived from Cox models.

Results: Of 359,310 individuals receiving one dose of Covid-19 vaccines, 160,327 (44.6%) were males, and the mean (SD) age at the vaccination date was 69.05 (8.04) years. After 28- and 90-days follow-up, 88 and 299 people developed VTE respectively, equivalent to an incidence of 0.88 (95% CI 0.70 to 1.08) and 0.92 (95% CI 0.82 to 1.04) per 100,000 person-days. The PRS was significantly associated with a higher risk of VTE (hazard ratio [HR] per 1 SD increase in PRS, 1.41 (95% CI 1.15 to 1.73) in 28 days and 1.36 (95% CI 1.22 to 1.52) in 90 days). Similar associations were found after stratification by vaccine type, in the two-dose cohort and across the historical unvaccinated cohorts.

Conclusions: The genetic predisposition to post-vaccination VTE is similar to that in historical data. This suggests that, at the population level, post-vaccination VTE has similar aetiology to conventional VTEs seen in the general population. In addition, the PRS-VTE associations were alike between people receiving adenovirus- and mRNA-based vaccines.