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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

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address:
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.
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pa.
Arizona Respiratory Center, University of Arizona, Tucson, Ariz.
Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tenn; Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark.
Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
Health Science Center at Houston, University of Texas, Houston, Tex.
Office of Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
Airways Biology Initiative, University of Pennsylvania Medical Center, Philadelphia, Pa.



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


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


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.


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.


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.


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

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