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

  1. Jessica Minnier
  2. Jennifer E Huffman
  3. Lina Gao
  4. Jacob Joseph
  5. Emily S Wan
  6. Wen-Chih Wu
  7. Ayako Suzuki
  8. Gita A Pathak
  9. Renato Polimanti
  10. Mehrdad Arjomandi
  11. Kyong-Mi Chang
  12. Helene Garcon
  13. Anurag Verma
  14. Yuk-Lam Ho
  15. James B Meigs
  16. Kelly Cho
  17. Robert A Bonomo
  18. Bryan R Gorman
  19. Saiju Pyarajan
  20. Elise Gatsby
  21. Nallakkandi Rajeevan
  22. Kristine E Lynch
  23. Julie A Lynch
  24. Seyedeh Maryam Zekavat
  25. Pradeep Natarajan
  26. Cecelia J Madison
  27. Jin J Zhou
  28. Darshana N Jhala
  29. Curtis J Donskey
  30. John E McGeary
  31. Peter D Reaven
  32. Yan V Sun
  33. Mat Freiberg
  34. Joel Gelernter
  35. Jeffrey M Petersen
  36. Adriana Hung
  37. Rose DL Huang
  38. Ravi K Madduri
  39. Sharvari Dalal
  40. Quinn S Wells
  41. Katherine P Liao
  42. Peter W.F. Wilson
  43. Philip S Tsao
  44. Christopher J O’Donnell
  45. John M Gaziano
  46. VA Million Veteran Program
  47. Richard L Hauger
  48. Sudha K. Iyengar
  49. Shiuh-Wen Luoh
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Abstract

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,F2G20210A were not significantly associated with the propensity of being tested for COVID-19. PRS(VTE) was significantly associated with a positive COVID-19 test inF5wild 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,F2G20210A 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 orF5wild 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 Points

  • Increased genetic predisposition to venous thrombosis is associated with increased COVID-19 positive testing rates.

  • PRS for VTE further risk stratifies factor V Leiden carriers regarding their VTE risk.

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