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 D.
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.
N1 - Funding Information:
M.J.M. is supported by a grant from the Parker B. Francis Foundation (principal investigator [PI]: McGeachie). A.C.W. is supported by NIH grant K08 HL088046 (PI: Wu). B.E.H. was funded by NIH grant K99 HL105663 (PI: Himes). PW was funded by an unrestricted research grant from the Tryg Foundation ( J.nr. 7343-09 , TrygFonden, Denmark). This work was further supported by NIH grants U01 HL065899 (PIs: Weiss and Tantisira), U19 HL065962 (PI: Roden), R01 NR013391 (PI: Tantisira), and R01 HL086601 (PI: Raby).
Funding Information:
We thank all CAMP subjects for their ongoing participation in this study. We acknowledge the CAMP investigators and research team, who were supported by the National Heart, Lung and Blood Institute, for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the CDNM of the Brigham and Women's Hospital under appropriate CAMP policies and human subject protections.
Funding Information:
Disclosure of potential conflict of interest: M. J. McGeachie has received research support from the National Institutes of Health (NIH)/National Heart Lung and Blood Institute (NHLBI; U01 HL065899) and the Parker B. Francis Foundation. A. C. Wu has received research support from the NIH/NHLBI, the NIH, the Agency for Healthcare Research and Quality, and the Harvard Pilgrim Health Care Institute and receives clinical revenue from Boston Children's Hospital. G. L. Clemmer has received research support from the NHLBI (U01 HL065899). J. Sordillo has received research support from the NIH (R00HL109162). B. E. Himes has received research support from the NIH/NHLBI. F. D. Martinez has received research support from the NIH (R01 HL056177, U10 HL098122, and P30 ES006694) and has received payment for lectures from Abbott. H. Xu has received research support from the NIH, the NHLBI (U19HL065962), and the Cancer Prevention and Research Institute of Texas (R1307); is on the Board of Scientific Counselors for the NIH–National Library of Medicine; has consultant arrangements with Vanderbilt University; and is employed by the University of Texas Health Science Center at Houston. R. A. Panettieri, Jr, has received research support from the NIH, AstraZeneca, Gilead, Johnson & Johnson, Merck, Roche, and Sanofi and has consultant arrangements with AstraZeneca, Johnson & Johnson, and Teva. B. A. Raby has received royalties from UpToDate. K. G. Tantisira has received research support from the NIH and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.
Publisher Copyright:
© 2015 American Academy of Allergy, Asthma & Immunology.
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 - CTNNA3
KW - SEMA3D
KW - biobank
KW - childhood asthma
KW - exacerbation
KW - expression quantitative trait locus
KW - genome-wide association study
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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 -