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

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 (N_cases = 4,325; N_controls = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10^-3) and joint meta-analyses with the HGI (N_cases = 13,320; N_controls = 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 (N_cases = 19,168/N_controls = 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 (N_cases = 44,820; N_controls = 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.

Keywords: coronavirus disease 2019; electronic health records; genetic association; idiopathic pulmonary fibrosis; severe acute respiratory syndrome coronavirus 2.

Figure 1.

Forest plot association of rs35705950-T in MUC5B with 1) COVID-19–positive participants versus population controls; 2) COVID-19–positive, hospitalized participants versus population controls, 3) COVID-19–positive, hospitalized participants versus COVID-19–positive participants who were not hospitalized, and 4) participants who were hospitalized for COVID-19 with high-flow oxygen or died of COVID-19 versus population controls. Odds ratio (OR) and 95% confidence interval (95% CI) are reported for the minor (T) allele, and results are shown for VA Million Veteran Program (MVP) African American (AFR), European American (EUR), and Hispanic/Latino American (HIS) participants and for multiancestry meta-analysis (ALL); the COVID-19 Host Genetics Initiative (HGI) multiancestry round 5 meta-analysis, excluding MVP and 23andMe; and the meta-analysis of MVP and HGI (META).

Figure 2.

Phenome-wide association study (PheWAS) of MUC5B rs35705950-T allele in the MVP. A PheWAS plot shows associations of rs35705950-T and phenotypes derived from electronic health records data before COVID-19 in MVP participants of European ancestry. The phenotypes are shown on the x axis and organized by disease categories. The P value (−log₁₀) of each association is shown on the y axis. The direction of the triangle represents the direction of effect of the associations, with the upward triangle indicating increased risk and the downward triangle indicating reduced risk. The red line indicates the significance threshold based on the Bonferroni correction. The forest plot of Bonferroni significant associations is shown at the right top corner of the PheWAS plot.