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http://purl.uniprot.org/citations/26073756http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26073756http://www.w3.org/2000/01/rdf-schema#comment"

Background

Asthma exacerbations are a major cause of morbidity and medical cost.

Objective

The objective of this study was to identify genetic predictors of exacerbations in asthmatic subjects.

Methods

We performed a genome-wide association study meta-analysis of acute asthma exacerbation in 2 pediatric clinical trials: the Childhood Asthma Management Program (n = 581) and the Childhood Asthma Research and Education (n = 205) network. Acute asthma exacerbations were defined as treatment with a 5-day course of oral steroids. We obtained a replication cohort from Biobank of Vanderbilt University Medical Center (BioVU; n = 786), the Vanderbilt University electronic medical record-linked DNA biobank. We used CD4(+) lymphocyte genome-wide mRNA expression profiling to identify associations of top single nucleotide polymorphisms with mRNA abundance of nearby genes.

Results

A locus in catenin (cadherin-associated protein), alpha 3 (CTNNA3), reached genome-wide significance (rs7915695, P = 2.19 × 10(-8); mean exacerbations, 6.05 for minor alleles vs 3.71 for homozygous major alleles). Among the 4 top single nucleotide polymorphisms replicated in BioVU, rs993312 in Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3D (SEMA3D) was significant (P = .0083) and displayed stronger association among African Americans (P = .0004 in BioVU [mean exacerbations, 3.91 vs 1.53]; P = .0089 in the Childhood Asthma Management Program [mean exacerbations, 6.0 vs 3.25]). CTNNA3 variants did not replicate in BioVU. A regulatory variant in the CTNNA3 locus was associated with CTNNA3 mRNA expression in CD4(+) cells from asthmatic patients (P = .00079). CTNNA3 appears to be active in the immune response, and SEMA3D has a plausible role in airway remodeling. We also provide a replication of a previous association of purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7), with asthma exacerbation.

Conclusions

We identified 2 loci associated with exacerbations through a genome-wide association study. CTNNA3 met genome-wide significance thresholds, and SEMA3D replicated in a clinical biobank database."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.org/dc/terms/identifier"doi:10.1016/j.jaci.2015.04.039"xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Xu H."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Tantisira K.G."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Weiss S.T."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Roden D.M."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Raby B.A."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Himes B.E."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Lasky-Su J."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Martinez F.D."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Denny J.C."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Wu A.C."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Panettieri R.A. Jr."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Shaffer C.M."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Weeke P."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Tse S.M."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Chase R.P."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Clemmer G.L."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"McGeachie M.J."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/author"Sordillo J."xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/name"J Allergy Clin Immunol"xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/pages"1503-1510"xsd:string
http://purl.uniprot.org/citations/26073756http://purl.uniprot.org/core/title"CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies."xsd:string
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