CTNNA3 and SEMA3D

Promising loci for asthma exacerbation identified through multiple genome-wide association studies

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1503-1510
Number of pages8
JournalJournal of Allergy and Clinical Immunology
Volume136
Issue number6
DOIs
StatePublished - Dec 1 2015

Fingerprint

Semaphorins
Genome-Wide Association Study
Asthma
Genome
Messenger RNA
Single Nucleotide Polymorphism
Alleles
Active Immunity
Purinergic P2X7 Receptors
Airway Remodeling
Catenins
Electronic Health Records
Cadherins
African Americans
Meta-Analysis
Steroids
Clinical Trials
Databases
Lymphocytes
Pediatrics

Keywords

  • Asthma
  • biobank
  • childhood asthma
  • CTNNA3
  • exacerbation
  • expression quantitative trait locus
  • genome-wide association study
  • SEMA3D

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mcgeachie, M. J., Wu, A. C., Tse, S. M., Clemmer, G. L., Sordillo, J., Himes, B. E., ... Tantisira, K. G. (2015). CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies. Journal of Allergy and Clinical Immunology, 136(6), 1503-1510. https://doi.org/10.1016/j.jaci.2015.04.039

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

In: Journal of Allergy and Clinical Immunology, Vol. 136, No. 6, 01.12.2015, p. 1503-1510.

Research output: Contribution to journalArticle

Mcgeachie, MJ, Wu, AC, Tse, SM, Clemmer, GL, Sordillo, J, Himes, BE, Lasky-Su, J, Chase, RP, Martinez, F, Weeke, P, Shaffer, CM, Xu, H, Denny, JC, Roden, DM, Panettieri, RA, Raby, BA, Weiss, ST & Tantisira, KG 2015, 'CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies', Journal of Allergy and Clinical Immunology, vol. 136, no. 6, pp. 1503-1510. https://doi.org/10.1016/j.jaci.2015.04.039
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 ; 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. / CTNNA3 and SEMA3D : Promising loci for asthma exacerbation identified through multiple genome-wide association studies. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 136, No. 6. pp. 1503-1510.
@article{ffa7e5ae57fa472c965e065f90974702,
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.",
keywords = "Asthma, biobank, childhood asthma, CTNNA3, exacerbation, expression quantitative trait locus, genome-wide association study, SEMA3D",
author = "Mcgeachie, {Michael J.} and Wu, {Ann C.} and Tse, {Sze Man} and Clemmer, {George L.} and Joanne Sordillo and Himes, {Blanca E.} and Jessica Lasky-Su and Chase, {Robert P.} and Fernando Martinez and Peter Weeke and Shaffer, {Christian M.} and Hua Xu and Denny, {Josh C.} and Roden, {Dan M.} and Panettieri, {Reynold A.} and Raby, {Benjamin A.} and Weiss, {Scott T.} and Tantisira, {Kelan G.}",
year = "2015",
month = "12",
day = "1",
doi = "10.1016/j.jaci.2015.04.039",
language = "English (US)",
volume = "136",
pages = "1503--1510",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "6",

}

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

UR - http://www.scopus.com/inward/record.url?scp=84948575251&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84948575251&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2015.04.039

DO - 10.1016/j.jaci.2015.04.039

M3 - Article

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 -