Network study of nasal transcriptome profiles reveals master regulator genes of asthma

Nasal transcriptomics can provide an accessible window into asthma pathobiology. Our goal was to move beyond gene signatures of asthma to identify master regulator genes that causally regulate genes associated with asthma phenotypes. We recruited 156 children with severe persistent asthma and contro...

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Vydané v:Journal of allergy and clinical immunology Ročník 147; číslo 3; s. 879 - 893
Hlavní autori: Do, Anh N., Chun, Yoojin, Grishina, Galina, Grishin, Alexander, Rogers, Angela J., Raby, Benjamin A., Weiss, Scott T., Vicencio, Alfin, Schadt, Eric E., Bunyavanich, Supinda
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 01.03.2021
Elsevier Limited
Predmet:
Adolescent
Age
Asthma
Asthma - genetics
Child
Children
Cohort Studies
Comparative analysis
Digital Object Identifier
Disease
Family medical history
Female
Forkhead Transcription Factors - genetics
Formins - genetics
Gene expression
Gene Expression Profiling
Humans
Inflammation
Intracellular Signaling Peptides and Proteins - genetics
Male
master regulator
mild persistent asthma
Models, Statistical
moderate persistent asthma
nasal
network
Nose - physiology
Phenotype
Phenotypes
probabilistic causal network
Quality control
severe persistent asthma
Spirometry
Transcriptome
Transcriptomes
New York
log2 FC
transcriptome
GO
KDA
WGCNA
Asthma
network
ATOM
nasal
master regulator
moderate persistent asthma
RNA-seq
FDR
mild persistent asthma
ARIA
probabilistic causal network
severe persistent asthma
gene expression
ISSN:0091-6749, 1097-6825, 1097-6825
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Popis
Shrnutí:Nasal transcriptomics can provide an accessible window into asthma pathobiology. Our goal was to move beyond gene signatures of asthma to identify master regulator genes that causally regulate genes associated with asthma phenotypes. We recruited 156 children with severe persistent asthma and controls for nasal transcriptome profiling and applied network-based and probabilistic causal methods to identify severe asthma genes and their master regulators. We then took the same approach in an independent cohort of 190 adults with mild/moderate asthma and controls to identify mild/moderate asthma genes and their master regulators. Comparative analysis of the master regulator genes followed by validation testing in independent children with severe asthma (n = 21) and mild/moderate asthma (n = 154) was then performed. Nasal gene signatures for severe persistent asthma and for mild/moderate persistent asthma were identified; both were found to be enriched in coexpression network modules for ciliary function and inflammatory response. By applying probabilistic causal methods to these gene signatures and validation testing in independent cohorts, we identified (1) a master regulator gene common to asthma across severity and ages (FOXJ1); (2) master regulator genes of severe persistent asthma in children (LRRC23, TMEM231, CAPS, PTPRC, and FYB); and (3) master regulator genes of mild/moderate persistent asthma in children and adults (C1orf38 and FMNL1). The identified master regulators were statistically inferred to causally regulate the expression of downstream genes that modulate ciliary function and inflammatory response to influence asthma. The identified master regulator genes of asthma provide a novel path forward to further uncovering asthma mechanisms and therapy. [Display omitted]
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0091-6749
1097-6825
1097-6825
DOI:10.1016/j.jaci.2020.07.006