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Publication Detail

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

Authors: McGeachie, Michael J; Wu, Ann C; Tse, Sze Man; Clemmer, George L; Sordillo, Joanne; Himes, Blanca E; Lasky-Su, Jessica; Chase, Robert P; Martinez, Fernando D; Weeke, Peter; Shaffer, Christian M; Xu, Hua; Denny, Josh C; Roden, Dan M; Panettieri Jr, Reynold A; Raby, Benjamin A; Weiss, Scott T; Tantisira, Kelan G

Published In J Allergy Clin Immunol, (2015 Dec)

Abstract: 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.

PubMed ID: 26073756 Exiting the NIEHS site

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*

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