Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
Abstract
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 102 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 28, 2022
- Source ID
- 10.1038/s41467-022-28973-7
Entities
People
- Ana Fairbanks-mahnke
- Angel C Mak
- Benjamin Saef
- Camille M Moore
- Celeste Eng
- Cydney L. Rios
- Deborah A. Nickerson
- Esteban G. Burchard
- Gonçalo Abecasis
- Hyun Min Kang
- Jamie L Everman
- Jennifer Elhawary
- Jose Rodriguez-santana
- Kenneth M Rice
- Max A Seibold
- Michael C. Zody
- Nathan D. Jackson
- Nhlbi Trans-omics For Precision Medicine (topmed) Consortium
- Noah A. Zaitlen
- Rajesh Kumar
- Sam S Oh
- Sandra Salazar
- Satria Sajuthi
- Scott Huntsman
- Søren Germer
- Vivian Medina
Organizations
- National Heart, Lung, and Blood Institute
- National Institute on Minority Health and Health Disparities
- United States Department of Defense
- United States Department of Health and Human Services