TY - JOUR
T1 - CTNNA3 and SEMA3D
T2 - Promising loci for asthma exacerbation identified through multiple genome-wide association studies
AU - Mcgeachie, Michael J.
AU - Wu, Ann C.
AU - Tse, Sze Man
AU - Clemmer, George L.
AU - Sordillo, Joanne
AU - Himes, Blanca E.
AU - Lasky-Su, Jessica
AU - Chase, Robert P.
AU - Martinez, Fernando
AU - Weeke, Peter
AU - Shaffer, Christian M.
AU - Xu, Hua
AU - Denny, Josh C.
AU - Roden, Dan M.
AU - Panettieri, Reynold A.
AU - Raby, Benjamin A.
AU - Weiss, Scott T.
AU - Tantisira, Kelan G.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
KW - Asthma
KW - biobank
KW - childhood asthma
KW - CTNNA3
KW - exacerbation
KW - expression quantitative trait locus
KW - genome-wide association study
KW - SEMA3D
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U2 - 10.1016/j.jaci.2015.04.039
DO - 10.1016/j.jaci.2015.04.039
M3 - Article
C2 - 26073756
AN - SCOPUS:84948575251
VL - 136
SP - 1503
EP - 1510
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 6
ER -