A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality

Our plain-English summary of A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality, by A. Verma, J. Minnier, E.S. Wan, et al (American Journal of Respiratory and Critical Care Medicine, 2022).

The study

• Authors: A. Verma, J. Minnier, E.S. Wan, J.E. Huffman, L. Gao, J. Joseph, Y.L. Ho, W.C. Wu, K. Cho, B.R. Gorman, N. Rajeevan, S. Pyarajan, H. Garcon, J.B. Meigs, Y.V. Sun, P.D. Reaven, J.E. McGeary, A. Suzuki, J. Gelernter, J.A. Lynch, J.M. Petersen, S.M. Zekavat, P. Natarajan, S. Dalal, D.N. Jhala, M. Arjomandi, E. Gatsby, K.E. Lynch, R.A. Bonomo, M. Freiberg, G.A. Pathak, J.J. Zhou, C.J. Donskey, R.K. Madduri, Q.S. Wells, R.D.L. Huang, R. Polimanti, K.M. Chang, K.P. Liao, P.S. Tsao, P.W.F. Wilson, A.M. Hung, C.J. O'Donnell, J.M. Gaziano, R.L. Hauger, S.K. Iyengar, S.W. Luoh, Million Veteran Program COVID-19 Science Initiative
• Journal: American Journal of Respiratory and Critical Care Medicine
• Published: 2022;206(10):1220-1229
• Type of article: Meta-analysis
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

In plain English

This genetic study asked whether rs35705950-T, a common MUC5B variant linked to idiopathic pulmonary fibrosis, was related to COVID-19 outcomes. It used U.S. veterans of European, African and Hispanic ancestry in the Million Veteran Program, with COVID-19 status from February 2020 to April 2021. Results were also combined with COVID-19 Host Genetics Initiative data. Asbestos exposure was not studied; asbestosis was only one of several adjustment factors in extra analyses. Across veteran ancestry groups, the variant was associated with fewer COVID-19 hospitalizations (odds ratio 0.89, 95% confidence interval 0.82 to 0.97). The combined figure was similar (0.90, 0.86 to 0.95). The variant was not associated with severe disease in veteran or combined analyses, or with death among veterans; Host Genetics Initiative data alone showed lower odds of severe disease (0.81, 0.73 to 0.90). Among European-ancestry veterans who tested positive, each variant copy was associated with lower odds of pneumonia within 60 days (0.82, 0.72 to 0.93). The authors concluded the variant may confer protection in COVID-19 hospitalizations. They noted that participants were mostly male and of European ancestry.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic association study using electronic health records of a biobank cohort (Million Veteran Program), analyzed by ancestry group, then meta-analyzed across ancestries and jointly with summary statistics from the COVID-19 Host Genetics Initiative
• Who was studied: U.S. veterans in the Million Veteran Program (658,582 participants in Table 1; 90% male) of European, African and Hispanic ancestry, including 19,168 who were COVID-19 positive, with COVID-19 status assessed February 2020 to April 2021. The joint analyses added Host Genetics Initiative data.
• Exposure: Carriage of the MUC5B rs35705950-T allele (0, 1 or 2 copies), directly genotyped. Asbestos exposure was not studied. A diagnosis of asbestosis was used only as an adjustment variable in sensitivity analyses, together with body mass index, Charlson comorbidity index, smoking history, rheumatoid arthritis with interstitial lung disease, and IPF.
• Main results:
  • In the cross-ancestry meta-analysis within the Million Veteran Program, the T allele was associated with fewer COVID-19 hospitalizations compared with population controls: OR 0.89 (0.82 to 0.97), P = 6.86 × 10^-3. Table 2 gives 4,234 cases and 507,640 controls; the abstract gives 4,325 cases.
  • In the joint meta-analysis with the Host Genetics Initiative (13,320 cases; 1,508,841 controls), hospitalization OR was 0.90 (0.86 to 0.95), P = 8.99 × 10^-5. This was the most significant association in the joint analysis.
  • The T allele was not associated with reduced COVID-19 positivity within the Million Veteran Program (P = 0.06). It was nominally significant in the joint meta-analysis with the Host Genetics Initiative (44,820 cases; 1,775,827 controls; OR 0.97, 0.95 to 1.00).
  • No association was found with severe COVID-19 in the veteran or combined analyses. Within the Million Veteran Program meta-analysis (947 severe cases), OR was 0.94 (0.79 to 1.12), P = 0.509. In the joint analysis with the Host Genetics Initiative, OR was 0.93 (0.79 to 1.1), P = 0.410.
  • In the Host Genetics Initiative meta-analysis alone (3,757 severe cases; 699,885 controls), the T allele was associated with lower odds of severe COVID-19: OR 0.81 (0.73 to 0.9), with a P value printed in damaged form, apparently 6.69 × 10^-5.
  • In sensitivity analyses among veterans tested for COVID-19 within the VA (n = 136,164), with extra adjustment including asbestosis, the T allele remained associated with reduced risk of hospitalization compared with non-hospitalization (OR 0.86, 0.77 to 0.95, P = 0.004). It was not associated with severe outcomes plus mortality (OR 0.89, 0.67 to 1.20, P = 0.45) or with mortality alone (OR 0.93, 0.74 to 1.17, P = 0.56).
  • Among participants of European ancestry who tested positive for COVID-19 (n = 8,541), the adjusted odds of pneumonia within 60 days were 18% lower for each additional T allele: OR 0.82 (0.72 to 0.93), P = 0.001. Among COVID-19-negative participants, the OR was 1.06 (0.98 to 1.15), P = 0.13, which was not significant. The interaction OR was 0.77 (0.66 to 0.89), P = 0.0004.
  • In pre-pandemic health record data, the T allele was associated with increased risk of 'postinflammatory pulmonary fibrosis' (OR 2.85, 2.65 to 3.05) and 'other alveolar and parietoalveolar pneumonopathy' (OR 2.64, 2.50 to 2.78) in all three ancestry groups. No significant association was found with influenza infection or bacterial pneumonia.
• The authors' conclusion: The authors concluded that the MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.
• Limitations the authors state:
  • Participants were predominantly male and of European ancestry, and the allele is less common in non-European groups. This may have limited the power to detect associations among women and racial/ethnic minorities.
  • Because of the timing of the data freeze, only short-term outcomes were captured.
  • Residual confounding and bias may still exist. This includes possible behavior changes, such as more testing or stricter self-isolation, among carriers of the variant.
  • Viral subtypes, vaccination status and treatment approaches changed over time, which may have affected severity outcomes.
  • The effect estimates were modest, which may limit use of the variant in clinical or predictive algorithms.
  • Post-COVID-19 pneumonia events in Hispanic or African ancestry individuals were too few to analyze.

Topics

Medical terms in this study, explained in our Lexicon: Idiopathic, Pulmonary Fibrosis, Meta-Analysis, Interstitial Lung Disease.

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