A MUC5Bgene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection

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

Rationale

A commonMUC5Bgene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear.

Objectives

To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI).

Methods

MVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of aMUC5Brs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2,and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions.

Measurements and Main Results

A COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement.

Conclusions

TheMUC5Bvariant rs35705950-T is protective in COVID-19 infection.

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