Publications

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 95 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology.

Nature Communications volume 13, Article number: 1632 (2022)

Authors

Other Contributors

Satria P. Sajuthi, Jamie L. Everman, Nathan D. Jackson, Benjamin Saef, Cydney L. Rios, Camille M. Moore, Angel C. Y. Mak, Celeste Eng, Ana Fairbanks-Mahnke, Sandra Salazar, Jennifer Elhawary, Scott Huntsman, Vivian Medina, Deborah A. Nickerson, Soren Germer, Michael C. Zody, Gonçalo Abecasis, Hyun Min Kang, Kenneth M. Rice, Rajesh Kumar, Noah A. Zaitlen, Sam Oh, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, José Rodríguez-Santana, Esteban G. Burchard & Max A. Seibold

 

  1. Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA

    Satria P. Sajuthi, Jamie L. Everman, Nathan D. Jackson, Benjamin Saef, Cydney L. Rios, Camille M. Moore, Ana Fairbanks-Mahnke & Max A. Seibold

  2. Department of Biomedical Research, National Jewish Health, Denver, CO, USA

    Camille M. Moore

  3. Department of Biostatistics and Informatics, University of Colorado, Denver, CO, USA

    Camille M. Moore

  4. Department of Medicine, University of California-San Francisco, San Francisco, CA, USA

    Angel C. Y. Mak, Celeste Eng, Sandra Salazar, Jennifer Elhawary, Scott Huntsman, Sam Oh & Esteban G. Burchard

  5. Centro de Neumología Pediátrica, San Juan, PR, USA

    Vivian Medina & José Rodríguez-Santana

  6. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    Deborah A. Nickerson

  7. New York Genome Center, New York, NY, USA

    Soren Germer & Michael C. Zody

  8. Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

    Gonçalo Abecasis & Hyun Min Kang

  9. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Kenneth M. Rice

  10. Ann and Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University, Chicago, IL, USA

    Rajesh Kumar

  11. Department of Neurology and Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Noah A. Zaitlen

  12. Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, San Francisco, CA, USA

    Esteban G. Burchard

  13. Department of Pediatrics, National Jewish Health, Denver, CO, USA

    Max A. Seibold

  14. Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA

    Max A. Seibold

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