Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use

Natalia Hernandez-Pacheco, Raquel Granell, Anke Maitland-van der Zee

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Abstract

Rationale Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.

Methods A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 European-descent children treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.

Results Ten independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10−6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078, p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.

Conclusions The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.
Original languageEnglish
Article number2003388
JournalEuropean Respiratory Journal
Volume57
Issue number5
Early online date20 Dec 2020
DOIs
Publication statusPublished - 13 May 2021

Bibliographical note

Funding Information:
N. Hernandez-Pacheco reports grants from Instituto de Salud Carlos III (ISCIII, FI16/00136) and co-funded by the European Social Funds from the European Union (ESF) ?ESF invests in your future?, during the conduct of the study. S.J. Vijverberg has nothing to disclose. E. Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation, and Universities (PRE2018-083837), during the conduct of the study. J. Li has nothing to disclose. Y.Y. Sio has nothing to disclose. R. Granell has nothing to disclose. A. Corrales has nothing to disclose. C. Maroteau has nothing to disclose. R. Lethem has nothing to disclose. J. Perez-Garcia has nothing to disclose. N. Farzan has nothing to disclose. K. Repnik has nothing to disclose. M. Gorenjak has nothing to disclose. P. Soares has nothing to disclose. L. Karimi has nothing to disclose. M. Schieck has nothing to disclose. L. P?rez-M?ndez has nothing to disclose. V. Berce has nothing to disclose. R. Tavendale has nothing to disclose. C. Eng has nothing to disclose. O. Sardon has nothing to disclose. I. Kull has nothing to disclose. S. Mukhopadhyay reports grants from The Gannochy Trust, Perth and Kinross City Council and Scottish Enterprises Tayside, during the conduct of the study. M. Pirmohamed reports grants from UK Department of Health and UK Medical Research Council, during the conduct of the study; grants from MRC Clinical Pharmacology Training Scheme (joint funding by MRC and Roche, UCB, Eli Lilly and Novartis), Joint PhD studentship funded by EPSRC and Astra Zeneca and grants from Bristol Myers Squibb, outside the submitted work. K. M.C. Verhamme reports grants from ZonMw, during the conduct of the study; and works for a department who in the past received unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis and GSK. E.G. Burchard reports grants from the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) (X01HL134589, X01HL134589,R01HL128439, R01HL135156, R01HL141992 and R01HL141845), the National Institute of Environmental Health Sciences (NIEHS) (R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443 and R56MD013312), the National Institute of General Medical Sciences (NIGMS) (RL5GM118984), the Tobacco-Related Disease Research Program (award numbers 24RT-0025 and 27IR-0030), the National Human Genome Research Institute (NHGRI) (U01HG009080), the Sandler Family Foundation, the American Asthma Foundation, the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, during the conduct of the study. M. Kabesch reports grants from European Union, German Ministry of Education and Research, German Research Foundation, during the conduct of the study; personal fees for consultancy from Bionorica, Sanofi, Novartis and Bencard, personal fees for lectures from ERS, EAACI, ATS, Novartis, Glaxo, Nutricia, Hipp and Allergopharma, outside the submitted work. D.B. Hawcutt has nothing to disclose. E. Mel?n has nothing to disclose. U. Poto?nik reports grants from Slovenian Research Agency (P3-0067) and Ministry of Education, Science and Sport Slovenia (MIZS) (SysPharmPediA grant C3330-16-500106), during the conduct of the study. F.T. Chew reports grants from Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore), during the conduct of the study; and consulting fees from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation and Olam International, outside the submitted work. K.G. Tantisira reports grants from U.S. National Institutes of Health, during the conduct of the study. S. Turner has nothing to disclose. C.M. Palmer has nothing to disclose. C. Flores has nothing to disclose. M. Pino-Yanes reports grants from Spanish Ministry of Economy, Industry and Competitiveness (funded by the Ram?n y Cajal Program, RYC-2015-17205), and Instituto de Salud Carlos III (ISCIII) (funded by ISCIII through AES and EC within AAL framework, and the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020, AC15/00015), during the conduct of the study. A.H. Maitland-van der Zee reports grants from GSK, during the conduct of the study; grants from Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and Boehringer Ingelheim, outside the submitted work. This study was supported by the awards (AC15/00015 and AC15/00058) funded 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 (M. Pino-Yanes, Olaia Sard?n), the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020, and by the Spanish Ministry of Science, Innovation and Universities (grant SAF2017?83417R MICIU/AEI/FEDER, UE). The PACMAN 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 number P3-0067) and from SysPharmPedia grant, co-financed by Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106). GALA II was supported by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported 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 and the National Institute of Environmental Health Sciences grant R01ES015794. SAGE was funded by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported 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. The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and established by funding from The Wellcome Trust Biomedical Resource (grant number 099177/Z/12/Z). Genotyping of samples from BREATHE-PAGES, GoSHARE, and SCSGES was carried out at CeGen-PRB3-ISCIII; supported by ISCIII and European Regional Development Fund (ERDF) (PT17/0019). ALSPAC was supported by the UK Medical Research Council and Wellcome (102215/2/13/2) and the University of Bristol. The Swedish Heart-Lung Foundation, the Swedish Research Council and Region Stockholm (ALF project and database maintenance) funded the BAMSE study. ESTATe was funded by an independent research grant by ZonMw project (113201006). The Childhood Asthma Management Program (CAMP) was supported by grants from NIH (R01HL127332 and R01NR013391). The PASS study was funded by the NHS Chair of Pharmacogenetics via the UK Department of Health. M. Pirmohamed is Emeritus NIHR Senior Investigator. Funding information for this article has been deposited with the Crossref Funder Registry.

Funding Information:
Support statement: This study was supported by the awards (AC15/00015 and AC15/00058) funded 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 (M. Pino-Yanes, Olaia Sardón), the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020, and by the Spanish Ministry of Science, Innovation and Universities (grant SAF2017–83417R MICIU/AEI/FEDER, UE). The PACMAN 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 number P3-0067) and from SysPharmPedia grant, co-financed by Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106). GALA II was supported by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported 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 and the National Institute of Environmental Health Sciences grant R01ES015794. SAGE was funded by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported 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. The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and established by funding from The Wellcome Trust Biomedical Resource (grant number 099177/Z/12/Z). Genotyping of samples from BREATHE-PAGES, GoSHARE, and SCSGES was carried out at CeGen-PRB3-ISCIII; supported by ISCIII and European Regional Development Fund (ERDF) (PT17/0019). ALSPAC was supported by the UK Medical Research Council and Wellcome (102215/2/13/2) and the University of Bristol. The Swedish Heart-Lung Foundation, the Swedish Research Council and Region Stockholm (ALF project and database maintenance) funded the BAMSE study. ESTATe was funded by an independent research grant by ZonMw project (113201006). The Childhood Asthma Management Program (CAMP) was supported by grants from NIH (R01HL127332 and R01NR013391). The PASS study was funded by the NHS Chair of Pharmacogenetics via the UK Department of Health. M. Pirmohamed is Emeritus NIHR Senior Investigator. Funding information for this article has been deposited with the Crossref Funder Registry.

Funding Information:
Acknowledgements: The authors acknowledge the patients, families, recruiters, healthcare providers and community clinics for their participation in all the studies included in the PiCA consortium (http://pica-consortium.org). The authors thank the contribution of Teide High-Performance Computing facilities (http://teidehpc.iter.es) provided by the Instituto Tecnológico y de Energías Renovables (ITER, S.A.) to the results of this research and also the Centro Nacional de Genotipado-Plataforma de Recursos Biomoleculares-Instituto de Salud Carlos III (CeGen-PRB3-ISCIII; www.cegen. org) for the genotyping services provided. We acknowledge all the families who took part in ALSPAC, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The GALA II and SAGE studies collaborators include Shannon Thyne (University of California Los Angeles ,Los Angeles, CA, USA), Harold J. Farber (Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA), Denise Serebrisky ( Jacobi Medical Center, New York, NY, USA), Rajesh Kumar (The Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA), Emerita Brigino-Buenaventura (Kaiser Permanente, Vallejo, CA, USA), Michael A. LeNoir (Bay Area Pediatrics, Oakland, CA, USA), Kelley Meade (Children’s Hospital and Research Center Oakland, Oakland, CA), William Rodriguez-Cintron (Veterans Caribbean Health Care System, San Juan, Puerto Rico), Pedro C. Avila (Northwestern University, Evanston, IL, USA), Jose R. Rodriguez-Santana (Centro de Neumologia Pediatrica, San Juan), Luisa N. Borrell (City University of New York, New York, NY) Adam Davis (Children’s Hospital and Research Center Oakland), Saunak Sen (University of Tennessee, Knoxville, TN, USA) and Fred Lurmann (Sonoma Technologies, Petaluma, CA, USA). The authors acknowledge the families and patients for their participation and thank the numerous healthcare providers and community clinics for their support and participation in the GALA II and SAGE studies. In particular, the authors thank study coordinator Sandra Salazar (University of California San Francisco, San Francisco, CA, USA); the recruiters who obtained the data: Duanny Alva, Gaby Ayala-Rodriguez, Lisa Caine, Elizabeth Castellanos, Jaime Colon, Denise DeJesus, Blanca Lopez, Brenda Lopez, Louis Martos, Vivian Medina, Juana Olivo, Mario Peralta, Esther Pomares, Jihan Quraishi, Johanna Rodriguez, Shahdad Saeedi, Dean Soto and Ana Taveras Conflict of interest: N. Hernandez-Pacheco reports grants from Instituto de Salud Carlos III (ISCIII, FI16/00136) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future”, during the conduct of the study. S.J. Vijverberg has nothing to disclose. E. Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation, and Universities (PRE2018-083837), during the conduct of the study. J. Li has nothing to disclose. Y.Y. Sio has nothing to disclose. R. Granell has nothing to disclose. A. Corrales has nothing to disclose. C. Maroteau has nothing to disclose. R. Lethem has nothing to disclose. J. Perez-Garcia has nothing to disclose. N. Farzan has nothing to disclose. K. Repnik has nothing to disclose. M. Gorenjak has nothing to disclose. P. Soares has nothing to disclose. L. Karimi has nothing to disclose. M. Schieck has nothing to disclose. L. Pérez-Méndez has nothing to disclose. V. Berce has nothing to disclose. R. Tavendale has nothing to disclose. C. Eng has nothing to disclose. O. Sardon has nothing to disclose. I. Kull has nothing to disclose. S. Mukhopadhyay reports grants from The Gannochy Trust, Perth and Kinross City Council and Scottish Enterprises Tayside, during the conduct of the study. M. Pirmohamed reports grants from UK Department of Health and UK Medical Research Council, during the conduct of the study; grants from MRC Clinical Pharmacology Training Scheme ( joint funding by MRC and Roche, UCB, Eli Lilly and Novartis), Joint PhD studentship funded by EPSRC and Astra Zeneca and grants from Bristol Myers Squibb, outside the submitted work. K. M.C. Verhamme reports grants from ZonMw, during the conduct of the study; and works for a department who in the past received unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis and GSK. E.G. Burchard reports grants from the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) (X01HL134589, X01HL134589,R01HL128439, R01HL135156, R01HL141992 and R01HL141845), the National Institute of Environmental Health Sciences (NIEHS) (R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443 and R56MD013312), the National Institute of General Medical Sciences (NIGMS) (RL5GM118984), the Tobacco-Related Disease Research Program (award numbers 24RT-0025 and 27IR-0030), the National Human Genome Research Institute (NHGRI) (U01HG009080), the Sandler Family Foundation, the American Asthma Foundation, the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, during the conduct of the study. M. Kabesch reports grants from European Union, German Ministry of Education and Research, German Research Foundation, during the conduct of the study; personal fees for consultancy from Bionorica, Sanofi, Novartis and Bencard, personal fees for lectures from ERS, EAACI, ATS, Novartis, Glaxo, Nutricia, Hipp and Allergopharma, outside the submitted work. D.B. Hawcutt has nothing to disclose. E. Melén has nothing to disclose. U. Potočnik reports grants from Slovenian Research Agency (P3-0067) and Ministry of Education, Science and Sport Slovenia (MIZS) (SysPharmPediA grant C3330-16-500106), during the conduct of the study. F.T. Chew reports grants from Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore), during the conduct of the study; and consulting fees from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation and Olam International, outside the submitted work. K.G. Tantisira reports grants from U.S. National Institutes of Health, during the conduct of the study. S. Turner has nothing to disclose. C.M. Palmer has nothing to disclose. C. Flores has nothing to disclose. M. Pino-Yanes reports grants from Spanish Ministry of Economy, Industry and Competitiveness (funded by the Ramón y Cajal Program, RYC-2015-17205), and Instituto de Salud Carlos III (ISCIII) (funded by ISCIII through AES and EC within AAL framework, and the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020, AC15/00015), during the conduct of the study. A.H. Maitland-van der Zee reports grants from GSK, during the conduct of the study; grants from Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and Boehringer Ingelheim, outside the submitted work.

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Structured keywords

  • ALSPAC

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