Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 03 2022
28 03 2022
Historique:
received:
08
09
2021
accepted:
10
02
2022
entrez:
29
3
2022
pubmed:
30
3
2022
medline:
14
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35347136
doi: 10.1038/s41467-022-28973-7
pii: 10.1038/s41467-022-28973-7
pmc: PMC8960819
doi:
Substances chimiques
Mucin 5AC
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1632Subventions
Organisme : NIEHS NIH HHS
ID : R01 ES015794
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL120393
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141992
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL107202
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL120393
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG006399
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008901
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141845
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135156
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG009080
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128439
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117626
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117004
Pays : United States
Organisme : NIMHD NIH HHS
ID : P60 MD006902
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL132821
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : NIMHD NIH HHS
ID : R01 MD010443
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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