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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Asthma / genetics*
  • Child
  • Child, Preschool
  • Female
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Male
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / metabolism
  • Semaphorins / genetics*
  • Sequence Analysis, RNA
  • Young Adult
  • alpha Catenin / genetics*


  • CTNNA3 protein, human
  • RNA, Messenger
  • Sema3D protein, human
  • Semaphorins
  • alpha Catenin