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

N. Hernandez-Pacheco, N. Farzan, B. Francis, L. Karimi, K. Repnik, S. J. Vijverberg, P. Soares, M. Schieck, M. Gorenjak, E. Forno, C. Eng, S. S. Oh, L. Pérez-Méndez, V. Berce, R. Tavendale, L. A. Samedy, S. Hunstman, D. Hu, K. Meade, H. J. Farber & 21 others P. C. Avila, D. Serebrisky, S. M. Thyne, E. Brigino-Buenaventura, W. Rodriguez-Cintron, S. Sen, R. Kumar, M. Lenoir, J. R. Rodriguez-Santana, J. C. Celedón, S. Mukhopadhyay, U. Potočnik, M. Pirmohamed, K. M. Verhamme, M. Kabesch, C. N. A. Palmer, D. B. Hawcutt, C. Flores, A. H. Maitland van der Zee, E. G. Burchard, M. Pino-Yanes

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Number of pages10
JournalClinical and Experimental Allergy
Early online date29 Jan 2019
DOIs
Publication statusE-pub ahead of print - 29 Jan 2019

Fingerprint

Genome-Wide Association Study
Adrenal Cortex Hormones
Asthma
Hispanic Americans
Population
African Americans
Intergenic DNA
Genetic Markers
Meta-Analysis
Therapeutics
Lung

Keywords

  • African American
  • Latino
  • childhood asthma
  • exacerbations
  • pharmacogenomics

Cite this

Hernandez-Pacheco, N., Farzan, N., Francis, B., Karimi, L., Repnik, K., Vijverberg, S. J., ... Pino-Yanes, M. (2019). Genome-wide association study of inhaled corticosteroid response in admixed children with asthma. Clinical and Experimental Allergy. https://doi.org/10.1111/cea.13354
Hernandez-Pacheco, N. ; Farzan, N. ; Francis, B. ; Karimi, L. ; Repnik, K. ; Vijverberg, S. J. ; Soares, P. ; Schieck, M. ; Gorenjak, M. ; Forno, E. ; Eng, C. ; Oh, S. S. ; Pérez-Méndez, L. ; Berce, V. ; Tavendale, R. ; Samedy, L. A. ; Hunstman, S. ; Hu, D. ; Meade, K. ; Farber, H. J. ; Avila, P. C. ; Serebrisky, D. ; Thyne, S. M. ; Brigino-Buenaventura, E. ; Rodriguez-Cintron, W. ; Sen, S. ; Kumar, R. ; Lenoir, M. ; Rodriguez-Santana, J. R. ; Celedón, J. C. ; Mukhopadhyay, S. ; Potočnik, U. ; Pirmohamed, M. ; Verhamme, K. M. ; Kabesch, M. ; Palmer, C. N. A. ; Hawcutt, D. B. ; Flores, C. ; van der Zee, A. H. Maitland ; Burchard, E. G. ; Pino-Yanes, M. / Genome-wide association study of inhaled corticosteroid response in admixed children with asthma. In: Clinical and Experimental Allergy. 2019.
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title = "Genome-wide association study of inhaled corticosteroid response in admixed children with asthma",
abstract = "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.",
keywords = "African American, Latino, childhood asthma, exacerbations, pharmacogenomics",
author = "N. Hernandez-Pacheco and N. Farzan and B. Francis and L. Karimi and K. Repnik and Vijverberg, {S. J.} and P. Soares and M. Schieck and M. Gorenjak and E. Forno and C. Eng and Oh, {S. S.} and L. P{\'e}rez-M{\'e}ndez and V. Berce and R. Tavendale and Samedy, {L. A.} and S. Hunstman and D. Hu and K. Meade and Farber, {H. J.} and Avila, {P. C.} and D. Serebrisky and Thyne, {S. M.} and E. Brigino-Buenaventura and W. Rodriguez-Cintron and S. Sen and R. Kumar and M. Lenoir and Rodriguez-Santana, {J. R.} and Celed{\'o}n, {J. C.} and S. Mukhopadhyay and U. Potočnik and M. Pirmohamed and Verhamme, {K. M.} and M. Kabesch and Palmer, {C. N. A.} and Hawcutt, {D. B.} and C. Flores and {van der Zee}, {A. H. Maitland} and Burchard, {E. G.} and M. Pino-Yanes",
note = "This work was supported by the award number AC15/00015 by the Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Programme framework (MP-Y), and the SysPharmPedia grant from the ERACoSysMed 1stJoint Transnational Call from the European Union under the Horizon 2020. N.H-P was funded by a fellowship (FI16/00136) from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future” and MP-Y was supported by the Ram{\'o}n y Cajal Program (RYC-2015-17205) by the Spanish Ministry of Economy, Industry and Competitiveness. The GALA II and SAGE studies were funded by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and DianaV. Hind Distinguished Professor in Pharmaceutical Sciences II, National Institutes of Health (1R01HL117004,R01Hl128439,R01HL135156, and 1X01HL134589),National Institute of Health and Environmental Health Sciences(R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (1P60MD006902,RL5GM118984, and1R01MD010443), andthe Tobacco-Related Disease Research Program under Award Number 24RT-0025to E.G.B. The PACMAN cohort study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The SLOVENIA study was financially supported by the Slovenian Research Agency (research core funding No. P3-0067) NH-P declares funding from Instituto de Salud Carlos III (ISCIII) and the European Social Funds. SSO and HF report funding from the National Institutes of Health (NIH). KV declares funding from ZonMw. MK reports funding from the European Union, the German Ministry of Education and Research, German Research Foundation and other sources. A-HM declares funding from GlaxoSmithKline, Boehringer Ingelheim and Astra Zeneca. EGB reports funding from NIH, National Institute of Health and Environmental Health Sciences, National Institute on Minority Health and Health Disparities and the Tobacco-Related Disease Research Program. MP-Y declares funding from ISCIII and Spanish Ministry of Economy, Industry and Competitiveness.The rest of authors have no conflict of interest.",
year = "2019",
month = "1",
day = "29",
doi = "10.1111/cea.13354",
language = "English",
journal = "Clinical and Experimental Allergy",
issn = "0954-7894",
publisher = "Wiley",

}

Hernandez-Pacheco, N, Farzan, N, Francis, B, Karimi, L, Repnik, K, Vijverberg, SJ, Soares, P, Schieck, M, Gorenjak, M, Forno, E, Eng, C, Oh, SS, Pérez-Méndez, L, Berce, V, Tavendale, R, Samedy, LA, Hunstman, S, Hu, D, Meade, K, Farber, HJ, Avila, PC, Serebrisky, D, Thyne, SM, Brigino-Buenaventura, E, Rodriguez-Cintron, W, Sen, S, Kumar, R, Lenoir, M, Rodriguez-Santana, JR, Celedón, JC, Mukhopadhyay, S, Potočnik, U, Pirmohamed, M, Verhamme, KM, Kabesch, M, Palmer, CNA, Hawcutt, DB, Flores, C, van der Zee, AHM, Burchard, EG & Pino-Yanes, M 2019, 'Genome-wide association study of inhaled corticosteroid response in admixed children with asthma', Clinical and Experimental Allergy. https://doi.org/10.1111/cea.13354

Genome-wide association study of inhaled corticosteroid response in admixed children with asthma. / Hernandez-Pacheco, N.; Farzan, N.; Francis, B.; Karimi, L.; Repnik, K.; Vijverberg, S. J.; Soares, P.; Schieck, M.; Gorenjak, M.; Forno, E.; Eng, C.; Oh, S. S.; Pérez-Méndez, L.; Berce, V.; Tavendale, R.; Samedy, L. A.; Hunstman, S.; Hu, D.; Meade, K.; Farber, H. J.; Avila, P. C.; Serebrisky, D.; Thyne, S. M.; Brigino-Buenaventura, E.; Rodriguez-Cintron, W.; Sen, S.; Kumar, R.; Lenoir, M.; Rodriguez-Santana, J. R.; Celedón, J. C.; Mukhopadhyay, S.; Potočnik, U.; Pirmohamed, M.; Verhamme, K. M.; Kabesch, M.; Palmer, C. N. A.; Hawcutt, D. B.; Flores, C.; van der Zee, A. H. Maitland; Burchard, E. G.; Pino-Yanes, M. (Lead / Corresponding author).

In: Clinical and Experimental Allergy, 29.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study of inhaled corticosteroid response in admixed children with asthma

AU - Hernandez-Pacheco, N.

AU - Farzan, N.

AU - Francis, B.

AU - Karimi, L.

AU - Repnik, K.

AU - Vijverberg, S. J.

AU - Soares, P.

AU - Schieck, M.

AU - Gorenjak, M.

AU - Forno, E.

AU - Eng, C.

AU - Oh, S. S.

AU - Pérez-Méndez, L.

AU - Berce, V.

AU - Tavendale, R.

AU - Samedy, L. A.

AU - Hunstman, S.

AU - Hu, D.

AU - Meade, K.

AU - Farber, H. J.

AU - Avila, P. C.

AU - Serebrisky, D.

AU - Thyne, S. M.

AU - Brigino-Buenaventura, E.

AU - Rodriguez-Cintron, W.

AU - Sen, S.

AU - Kumar, R.

AU - Lenoir, M.

AU - Rodriguez-Santana, J. R.

AU - Celedón, J. C.

AU - Mukhopadhyay, S.

AU - Potočnik, U.

AU - Pirmohamed, M.

AU - Verhamme, K. M.

AU - Kabesch, M.

AU - Palmer, C. N. A.

AU - Hawcutt, D. B.

AU - Flores, C.

AU - van der Zee, A. H. Maitland

AU - Burchard, E. G.

AU - Pino-Yanes, M.

N1 - This work was supported by the award number AC15/00015 by the Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Programme framework (MP-Y), and the SysPharmPedia grant from the ERACoSysMed 1stJoint Transnational Call from the European Union under the Horizon 2020. N.H-P was funded by a fellowship (FI16/00136) from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future” and MP-Y was supported by the Ramón y Cajal Program (RYC-2015-17205) by the Spanish Ministry of Economy, Industry and Competitiveness. The GALA II and SAGE studies were funded by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and DianaV. Hind Distinguished Professor in Pharmaceutical Sciences II, National Institutes of Health (1R01HL117004,R01Hl128439,R01HL135156, and 1X01HL134589),National Institute of Health and Environmental Health Sciences(R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (1P60MD006902,RL5GM118984, and1R01MD010443), andthe Tobacco-Related Disease Research Program under Award Number 24RT-0025to E.G.B. The PACMAN cohort study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The SLOVENIA study was financially supported by the Slovenian Research Agency (research core funding No. P3-0067) NH-P declares funding from Instituto de Salud Carlos III (ISCIII) and the European Social Funds. SSO and HF report funding from the National Institutes of Health (NIH). KV declares funding from ZonMw. MK reports funding from the European Union, the German Ministry of Education and Research, German Research Foundation and other sources. A-HM declares funding from GlaxoSmithKline, Boehringer Ingelheim and Astra Zeneca. EGB reports funding from NIH, National Institute of Health and Environmental Health Sciences, National Institute on Minority Health and Health Disparities and the Tobacco-Related Disease Research Program. MP-Y declares funding from ISCIII and Spanish Ministry of Economy, Industry and Competitiveness.The rest of authors have no conflict of interest.

PY - 2019/1/29

Y1 - 2019/1/29

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.

KW - African American

KW - Latino

KW - childhood asthma

KW - exacerbations

KW - pharmacogenomics

UR - http://www.scopus.com/inward/record.url?scp=85061585893&partnerID=8YFLogxK

U2 - 10.1111/cea.13354

DO - 10.1111/cea.13354

M3 - Article

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

SN - 0954-7894

ER -