TY - JOUR
T1 - Genome-wide association study of inhaled corticosteroid response in admixed children with asthma
AU - Hernandez-Pacheco, Natalia
AU - Farzan, Niloufar
AU - Francis, Ben
AU - Karimi, Leila
AU - Repnik, Katja
AU - Vijverberg, Susanne J.
AU - Soares, Patricia
AU - Schieck, Maximilian
AU - Gorenjak, Mario
AU - Forno, Erick
AU - Eng, Celeste
AU - Oh, Sam S.
AU - Pérez-Méndez, Lina
AU - Berce, Vojko
AU - Tavendale, Roger
AU - Samedy, Lesly-Anne
AU - Hunstman, Scott
AU - Hu, Donglei
AU - Meade, Kelley
AU - Farber, Harold J.
AU - Avila, Pedro C.
AU - Serebrisky, Denise
AU - Thyne, Shannon M.
AU - Brigino-Buenaventura, Emerita
AU - Rodriguez-Cintron, William
AU - Sen, Saunak
AU - Kumar, Rajesh
AU - Lenoir, Michael
AU - Rodriguez-Santana, Jose R.
AU - Celedón, Juan C.
AU - Mukhopadhyay, Somnath
AU - Potočnik, Uroš
AU - Pirmohamed, Munir
AU - Verhamme, Katia M.
AU - Kabesch, Michael
AU - Palmer, Colin N. A.
AU - Hawcutt, Daniel B.
AU - Flores, Carlos
AU - Maitland-van der Zee, Anke H.
AU - Burchard, Esteban G.
AU - Pino-Yanes, Maria
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85061585893&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30697902
U2 - https://doi.org/10.1111/cea.13354
DO - https://doi.org/10.1111/cea.13354
M3 - Article
C2 - 30697902
SN - 0954-7894
VL - 49
SP - 789
EP - 798
JO - Clinical and experimental allergy
JF - Clinical and experimental allergy
IS - 6
ER -