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

McGeachie MJ, Wu AC, Tse SM, Clemmer GL, Sordillo J, Himes BE, Lasky-Su J, Chase RP, Martinez FD, Weeke P, Shaffer CM, Xu H, Denny JC, Roden DM, Panettieri RA, Raby BA, Weiss ST, Tantisira KG
J Allergy Clin Immunol. 2015 136 (6): 1503-1510

PMID: 26073756 · PMCID: PMC4676949 · DOI:10.1016/j.jaci.2015.04.039

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.

Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

MeSH Terms (16)

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

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