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J Allergy Clin Immunol. 2015 Dec;136(6):1503-1510. doi: 10.1016/j.jaci.2015.04.039. Epub 2015 Jun 12.

CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies.

Author information

1
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address: michael.mcgeachie@channing.harvard.edu.
2
Center for Child Health Care Studies, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Mass; Division of General Pediatrics, Department of Pediatrics, Children's Hospital, Boston, Mass.
3
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
4
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pa.
5
Arizona Respiratory Center, University of Arizona, Tucson, Ariz.
6
Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tenn; Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark.
7
Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
8
Health Science Center at Houston, University of Texas, Houston, Tex.
9
Office of Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
10
Airways Biology Initiative, University of Pennsylvania Medical Center, Philadelphia, Pa.

Abstract

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.

KEYWORDS:

Asthma; CTNNA3; SEMA3D; biobank; childhood asthma; exacerbation; expression quantitative trait locus; genome-wide association study

PMID:
26073756
PMCID:
PMC4676949
DOI:
10.1016/j.jaci.2015.04.039
[Indexed for MEDLINE]
Free PMC Article

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