title: CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies.
abstract: 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.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address: michael.mcgeachie@channing.harvard.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGeachie
authors.affiliation: Center for Child Health Care Studies, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Mass; Division of General Pediatrics, Department of Pediatrics, Children's Hospital, Boston, Mass.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Wu
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: Sze Man
authors.initials: SM
authors.lastname: Tse
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: George L
authors.initials: GL
authors.lastname: Clemmer
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: Joanne
authors.initials: J
authors.lastname: Sordillo
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Chase
authors.affiliation: Arizona Respiratory Center, University of Arizona, Tucson, Ariz.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.affiliation: Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tenn; Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Weeke
authors.affiliation: Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Shaffer
authors.affiliation: Health Science Center at Houston, University of Texas, Houston, Tex.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Josh C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Office of Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Airways Biology Initiative, University of Pennsylvania Medical Center, Philadelphia, Pa.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass.
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D055815:Young Adult; D051178:alpha Catenin / Q000235:genetics*
chemical_list: C441963:CTNNA3 protein, human; D012333:RNA, Messenger; C000592402:Sema3D protein, human; D039961:Semaphorins; D051178:alpha Catenin
keywords: Asthma; CTNNA3; SEMA3D; biobank; childhood asthma; exacerbation; expression quantitative trait locus; genome-wide association study