Genome‐wide association study of inhaled corticosteroid response in admixed children with asthma

Summary Background Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Amer...

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Published inClinical and experimental allergy Vol. 49; no. 6; pp. 789 - 798
Main Authors Hernandez‐Pacheco, Natalia, Farzan, Niloufar, Francis, Ben, Karimi, Leila, Repnik, Katja, Vijverberg, Susanne J., Soares, Patricia, Schieck, Maximilian, Gorenjak, Mario, Forno, Erick, Eng, Celeste, Oh, Sam S., Pérez‐Méndez, Lina, Berce, Vojko, Tavendale, Roger, Samedy, Lesly‐Anne, Hunstman, Scott, Hu, Donglei, Meade, Kelley, Farber, Harold J., Avila, Pedro C., Serebrisky, Denise, Thyne, Shannon M., Brigino‐Buenaventura, Emerita, Rodriguez‐Cintron, William, Sen, Saunak, Kumar, Rajesh, Lenoir, Michael, Rodriguez‐Santana, Jose R., Celedón, Juan C., Mukhopadhyay, Somnath, Potočnik, Uroš, Pirmohamed, Munir, Verhamme, Katia M., Kabesch, Michael, Palmer, Colin N. A., Hawcutt, Daniel B., Flores, Carlos, Maitland‐van der Zee, Anke H., Burchard, Esteban G., Pino‐Yanes, Maria
Format Journal Article
LanguageEnglish
Published England Wiley Subscription Services, Inc 01.06.2019
Subjects
Administration, Inhalation
Adolescent
Adrenal Cortex Hormones - administration & dosage
African American
African Americans
Asthma
Asthma - genetics
Asthma - metabolism
Child
childhood asthma
Children
Corticosteroids
Cytidine Deaminase - genetics
DNA-Binding Proteins - genetics
exacerbations
Female
Genetic analysis
Genetic diversity
Genetic markers
Genome-wide association studies
Genome-Wide Association Study
Genomes
GTPase-Activating Proteins - genetics
Humans
Latino
Male
Minor Histocompatibility Antigens - genetics
Patients
pharmacogenomics
Replication
Respiratory function
pharmacogenomics
childhood asthma
Latino
exacerbations
African American
Online AccessGet full text
ISSN0954-7894
1365-2222
1365-2222
DOI10.1111/cea.13354

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Abstract Summary Background Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome‐wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. Objective We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. Methods A meta‐analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10−6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. Results A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10−6). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10−3) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10−3). Additionally, the reported association of the L3MBTL4‐ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. Conclusions and clinical relevance This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
AbstractList BackgroundInhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome‐wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.ObjectiveWe aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.MethodsA meta‐analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10−6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.ResultsA total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10−6). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10−3) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10−3). Additionally, the reported association of the L3MBTL4‐ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.Conclusions and clinical relevanceThis study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
Summary Background Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome‐wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. Objective We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. Methods A meta‐analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10−6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. Results A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10−6). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10−3) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10−3). Additionally, the reported association of the L3MBTL4‐ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. Conclusions and clinical relevance This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.BACKGROUNDInhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.OBJECTIVEWe aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.METHODSA meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.RESULTSA total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.CONCLUSIONS AND CLINICAL RELEVANCEThis study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
Author Farzan, Niloufar
Francis, Ben
Lenoir, Michael
Hunstman, Scott
Meade, Kelley
Soares, Patricia
Eng, Celeste
Vijverberg, Susanne J.
Sen, Saunak
Celedón, Juan C.
Kumar, Rajesh
Berce, Vojko
Hawcutt, Daniel B.
Hernandez‐Pacheco, Natalia
Thyne, Shannon M.
Pérez‐Méndez, Lina
Avila, Pedro C.
Flores, Carlos
Burchard, Esteban G.
Rodriguez‐Santana, Jose R.
Mukhopadhyay, Somnath
Verhamme, Katia M.
Rodriguez‐Cintron, William
Pirmohamed, Munir
Schieck, Maximilian
Gorenjak, Mario
Brigino‐Buenaventura, Emerita
Maitland‐van der Zee, Anke H.
Forno, Erick
Serebrisky, Denise
Hu, Donglei
Palmer, Colin N. A.
Potočnik, Uroš
Kabesch, Michael
Oh, Sam S.
Farber, Harold J.
Pino‐Yanes, Maria
Repnik, Katja
Samedy, Lesly‐Anne
Karimi, Leila
Tavendale, Roger
AuthorAffiliation 3 Department of Respiratory Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands
25 Department of Allergy and Immunology, Vallejo, California, United States
31 Centro de Neumología Pediátrica, San Juan, Puerto Rico
33 Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Regensburg, Germany
32 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
12 Division of Pediatric Pulmonary Medicine, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
16 Department of Pediatrics, University Medical Centre Maribor, Maribor, Slovenia
10 Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Regensburg, Germany
26 Veterans Caribbean Health Care System, San Juan, Puerto Rico
28 Feinberg School of Medicine’s Di
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– name: 11 Department of Human Genetics, Hannover Medical School, Hannover, Germany
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– name: 29 Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States
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– name: 16 Department of Pediatrics, University Medical Centre Maribor, Maribor, Slovenia
– name: 26 Veterans Caribbean Health Care System, San Juan, Puerto Rico
– name: 33 Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Regensburg, Germany
– name: 35 Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
– name: 2 Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
– name: 14 Department of Clinic Epidemiology and Biostatistics, Research Unit, Hospital Universitario N.S. de Candelaria, Gerencia de Atención Primaria, Santa Cruz de Tenerife, Spain
– name: 15 CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
– name: 18 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States
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– name: 3 Department of Respiratory Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands
– name: 13 Department of Medicine, University of California, San Francisco, San Francisco, California, United States
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  organization: Baylor College of Medicine and Texas Children's Hospital
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  surname: Celedón
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  surname: Mukhopadhyay
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  organization: University of Dundee
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  surname: Pirmohamed
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  organization: University of Liverpool
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  givenname: Katia M.
  surname: Verhamme
  fullname: Verhamme, Katia M.
  organization: Erasmus University Medical Center
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  givenname: Michael
  surname: Kabesch
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  organization: University Children's Hospital Regensburg (KUNO)
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  organization: Alder Hey Children's Hospital
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  fullname: Maitland‐van der Zee, Anke H.
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  surname: Pino‐Yanes
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  email: mdelpino@ull.edu.es
  organization: Instituto de Salud Carlos III
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30697902$$D View this record in MEDLINE/PubMed
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Snippet Summary Background Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However,...
Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children...
BackgroundInhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many...
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StartPage 789
SubjectTerms Administration, Inhalation
Adolescent
Adrenal Cortex Hormones - administration & dosage
African American
African Americans
Asthma
Asthma - genetics
Asthma - metabolism
Child
childhood asthma
Children
Corticosteroids
Cytidine Deaminase - genetics
DNA-Binding Proteins - genetics
exacerbations
Female
Genetic analysis
Genetic diversity
Genetic markers
Genome-wide association studies
Genome-Wide Association Study
Genomes
GTPase-Activating Proteins - genetics
Humans
Latino
Male
Minor Histocompatibility Antigens - genetics
Patients
pharmacogenomics
Replication
Respiratory function
Title Genome‐wide association study of inhaled corticosteroid response in admixed children with asthma
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fcea.13354
https://www.ncbi.nlm.nih.gov/pubmed/30697902
https://www.proquest.com/docview/2233695994
https://www.proquest.com/docview/2179531904
https://pubmed.ncbi.nlm.nih.gov/PMC7054824
Volume 49
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