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

• Type of Material: Article
• Authors: Anurag Verma, Corporal Michael J Crescenz VA Medical Center; Jessica Minnier, Oregon Health and Science University; Emily S. Wan, VA Boston Healthcare System; Jennifer E. Huffman, VA Boston Healthcare System; Lina Gao, Oregon Health and Science University; Jacov Joseph, VA Boston Healthcare System; Yuk-Lam Ho, VA Boston Healthcare System; Wen-Chih Wu, Providence VA Healthcare System; Peter Wilson, Emory University; Shiuh-Wen Luoh, Oregon Health and Science University
• Language: English
• Date: 2022-11-15
• Publisher: AMER THORACIC SOC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the American Thoracic Society
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1164/rccm.202109-2166OC
• Title of Journal or Parent Work: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
• Volume: 206
• Issue: 10
• Start Page: 1220
• End Page: 1229
• Grant/Funding Information: Supported by an MVP035 award from the Million Veteran Program, Office of Research and Development, Veterans Health Administration; an MVP008 award (1I01BX004188-01) (S.-W.L.), Veterans Affairs of the United States Government BX 004831 (P.W.F.W. and K.C.); National Institutes of Health grant R01GM138597 (A.V.); and National Heart, Lung, and Blood Institute Grants R01HL142711; and R01HL127564 (P.N.). This publication does not represent the views of the Department of Veterans Affairs of the U.S. Government.
• Keywords: Respiratory System; General & Internal Medicine; Critical Care Medicine; severe acute respiratory syndrome coronavirus 2; ASSOCIATION; PNEUMONIA; genetic association; SURVIVAL; IDIOPATHIC PULMONARY-FIBROSIS; Life Sciences & Biomedicine; HEALTH; coronavirus disease 2019; idiopathic pulmonary fibrosis; PROMOTER POLYMORPHISM; DISTAL AIRWAYS; RISK; electronic health records; Science & Technology
• Research Categories: Biology, Virology; Health Sciences, Public Health

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 3 1023) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86–0.95]; P = 8.99 3 1025). 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.