Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28973-7
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Funding
- NIH [R01 HL135156, R01 MD010443, R01 HL128439, P01 HL132821, P01 HL107202, R01 HL117004, R01 128439, R01 HL141992, R01 HL141845]
- DOD [W81WH-16-2-0018]
- Sandler Family Foundation
- American Asthma Foundation
- RWJF Amos Medical Faculty Development Program
- National Heart, Lung, and Blood Institute (NHLBI) [R01HL117004, R01HL128439, R01HL135156, X01HL134589]
- National Institute of Environmental Health Sciences [R01ES015794]
- National Institute on Minority Health and Health Disparities (NIMHD) [P60MD006902, R01MD010443]
- National Human Genome Research Institute [U01HG009080]
- Tobacco-Related Disease Research Program [24RT-0025, 27IR-0030]
- National Heart, Lung and Blood Institute (NHLBI)
- TOPMed Informatics Research Center [3R01HL-117626-02S1, HHSN268201800002I]
- New York Genome Center under The Centers for Common Disease Genomics of the Genome Sequencing Program (GSP) [UM1 HG008901]
- National Human Genome Research Institute
- National Heart, Lung, and Blood Institute
- National Eye Institute
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By performing a transcriptome-wide association study, the researchers identified genetic determinants of airway dysfunction in asthma and discovered genetic mechanisms related to 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. Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
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