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
N1 - Funding Information:
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 1st Joint 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 Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, National Institutes of Health (1R01HL117004, R01Hl128439, R01HL135156 and 1X0 1HL134589), National Institute of Health and Environmental Health Sciences (R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (1P60MD006902, RL5GM118984 and 1R01MD010443) and the Tobacco‐Related Disease Research Program under Award Number 24RT‐0025 to 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).
Funding Information:
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.
Funding Information:
Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research and European Community (EC) (AES), Grant/ Award Number: AC15/00015; ISCIII and European Social Funds from the European Union (ESF), Grant/Award Number: FI16/ 00136; ERACoSysMed 1st Joint Transnational Call from the European Union; Spanish Ministry of Economy, Industry and Competitiveness, Ramón y Cajal Program, Grant/Award Number: RYC-2015-17205; Sandler Family Foundation; the American Asthma Foundation; the RWJF Amos Medical Faculty Development Program; Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II; National Institutes of Health, Grant/Award Number: 1R01HL117004, R01Hl128439, R01HL135156, 1X01HL134589; National Institute of Health and Environmental Health Sciences, Grant/Award Number: R01ES015794, R21ES24844; the National Institute on Minority Health and Health Disparities, Grant/Award Number: 1P60MD006902, RL5GM118984, 1R01MD010443; the Tobacco-Related Disease Research Program, Grant/Award Number: 24RT-0025; Strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences; Slovenian Research Agency, Grant/Award Number: P3-0067
Funding Information:
The authors acknowledge the patients, families, recruiters, healthcare providers and community clinics for their participation in all the studies involved in the PiCA consortium (http://pica-consortium.org/). The authors also thank Sandra Salazar for her support as the GALA II and SAGE study coordinator and the contribution of Teide High-Performance Computing facilities (http://teidehpc.iter.es) provided by the Instituto Tecnol?gico y de Energ?as Renovables (ITER, S.A.) to the results of this research. 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 1st Joint 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?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 Diana V. 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 and?1R01MD010443) and?the Tobacco-Related Disease Research Program under Award Number 24RT-0025?to 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).
Publisher Copyright:
© 2019 John Wiley & Sons Ltd
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.
KW - African American
KW - Latino
KW - childhood asthma
KW - exacerbations
KW - pharmacogenomics
UR - http://www.scopus.com/inward/record.url?scp=85061585893&partnerID=8YFLogxK
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U2 - 10.1111/cea.13354
DO - 10.1111/cea.13354
M3 - Article
C2 - 30697902
AN - SCOPUS:85061585893
VL - 49
SP - 789
EP - 798
JO - Clinical and Experimental Allergy
JF - Clinical and Experimental Allergy
SN - 0954-7894
IS - 6
ER -