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

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 6; pp. 1503 - 1510
• Main 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, Reynold A., Raby, Benjamin A., Weiss, Scott T., Tantisira, Kelan G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2015; Elsevier Limited
• Subjects: Adolescent; Adult; Algorithms; Allergy and Immunology; alpha Catenin - genetics; Asthma; Asthma - genetics; biobank; Child; Child, Preschool; childhood asthma; Clinical trials; CTNNA3; exacerbation; expression quantitative trait locus; Female; Gene expression; Gene loci; Genome-Wide Association Study; Genomes; Humans; Infant; Male; Medical records; Pediatrics; Polymorphism, Single Nucleotide; RNA, Messenger - metabolism; SEMA3D; Semaphorins - genetics; Sequence Analysis, RNA; Studies; Young Adult; GWAS; SEMA3D; PACT; childhood asthma; CARE; TTN; SNP; CTNNA3; ASM; CLIC; biobank; CAMP; eQTL; Asthma; exacerbation; CEBP; ABRIDGE; P2RX7; expression quantitative trait locus; BioVU; MARS; genome-wide association study; ICS; LD; CDNM; Asthma BioRepository for Integrative Genomic Exploration; Linkage disequilibrium; Purinergic receptor P2X, ligand-gated ion channel, 7; CCAAT/enhancer-binding protein; Catenin (cadherin-associated protein), alpha 3; Airway smooth muscle; Childhood Asthma Research and Education; Montelukast or Azithromycin for Reduction of Inhaled Corticosteroids in Childhood Asthma Study; Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3D; Biobank of Vanderbilt University Medical Center; Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid; Childhood Asthma Management Program; Inhaled corticosteroid; Pediatric Asthma Controller Trial; Titin; Channing Division of Network Medicine; Single nucleotide polymorphism
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.04.039

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.