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, 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 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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  1. ScreenIT

    SciScore for 10.1101/2022.01.29.22270094: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Study design and participants: This study included 464,961 participants from the Million Veteran Program who had European ancestry with available genetic data (release 4), 108,437 of which were tested for COVID-19.
    Million Veteran Program
    suggested: (Million Veteran Program, RRID:SCR_021731)
    Data Sharing Statement: Full GWAS summary statistics from published MVP investigations are available in dbGaP (https://www.ncbi.nlm.nih.gov/gap) under the MVP accession (phs001672).
    https://www.ncbi.nlm.nih.gov/gap
    suggested: (NCBI database of Genotypes and Phenotypes, RRID:SCR_002709)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Study limitations are that only European ancestry participants were studied as PRS(VTE) was developed within cohorts of European ancestry. Only patients that were COVID-19 tested were included in this study. The last patients that were tested in the study cohort were on June 1 2021 so vaccination status might play a role in the study. The serotype of viruses involved was not known. Treatment modalities had evolved during the study period. Diagnosis of clinical events in the immediate post index period might be affected by potential underutilization of imaging modalities required to make certain diagnoses. The latter was expected to dissipate however after a recommended short period of quarantine and with longer follow up. An important consideration in the issue of testing positive rates was exposure. It is unlikely that PRS(VTE) was associated with differential environmental exposure however. Strengths include a large sample size and geographically diverse population evaluated, the prospective nature of this study to examine testing (positive) rates and clinical sequelae of COVID-19 infection, and the use of genetic stratification to investigate post COVID-19 events. In summary, PRS(VTE) was associated with COVID-19 positive testing rates for EUR in this large prospective cohort from the MVP. The linkage of COVID-19 infection with thromboembolism processes is novel and may reveal mechanisms of early steps of viral infection and/or treatment and prevention strategies.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2022.01.29.22270094v1 on medRxiv