Natalia Hernandez-Pacheco1,2, Susanne J Vijverberg3,4,5, Esther Herrera-Luis2, Jiang Li6, Yang Yie Sio7, Raquel Granell8, Almudena Corrales1,9, Cyrielle Maroteau10, Ryan Lethem8, Javier Perez-Garcia2, Niloufar Farzan3,4,11, Katja Repnik12,13, Mario Gorenjak12, Patricia Soares14,15, Leila Karimi16, Maximilian Schieck17,18, Lina Pérez-Méndez1,9,19, Vojko Berce12,20, Roger Tavendale21, Celeste Eng22, Olaia Sardon23,24, Inger Kull25, Somnath Mukhopadhyay14,21, Munir Pirmohamed26, Katia M C Verhamme16, Esteban G Burchard22,27, Michael Kabesch17, Daniel B Hawcutt28,29, Erik Melén25,30, Uroš Potočnik12,13, Fook Tim Chew7, Kelan G Tantisira6,31, Steve Turner32, Colin N Palmer21, Carlos Flores1,9,33,34, Maria Pino-Yanes35,2,9,34,36, Anke H Maitland-van der Zee3,4,5,36. 1. Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. 2. Genomics and Health Group, Dept of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, San Cristóbal de La Laguna, Spain. 3. Dept of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 4. Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Utrecht, The Netherlands. 5. Dept of Paediatric Respiratory Medicine and Allergy, Emma's Children Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 6. The Channing Division of Network Medicine, Dept of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 7. Dept of Biological Sciences, National University of Singapore, Singapore, Singapore. 8. MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 9. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 10. Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK. 11. Breathomix B.V., El Reeuwijk, The Netherlands. 12. Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Maribor, Slovenia. 13. Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia. 14. Academic Dept of Paediatrics, Brighton and Sussex Medical School, Royal Alexandra Children's Hospital, Brighton, UK. 15. Escola Nacional de Saúde Pública, Lisboa, Portugal. 16. Dept of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands. 17. Dept of Paediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany. 18. Dept of Human Genetics, Hannover Medical School, Hannover, Germany. 19. Dept of Clinic Epidemiology and Biostatistics, Research Unit, Hospital Universitario N.S. de Candelaria, Gerencia de Atención Primaria, Santa Cruz de Tenerife, Spain. 20. Dept of Paediatrics, University Medical Centre Maribor, Maribor, Slovenia. 21. Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. 22. Dept of Medicine, University of California, San Francisco, San Francisco, CA, USA. 23. Division of Paediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain. 24. Dept of Paediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain. 25. Dept of Clinical Sciences and Education Södersjukhuset, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden. 26. Dept of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 27. Dept of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. 28. Dept of Women's and Children's Health, University of Liverpool, Liverpool, UK. 29. Alder Hey Children's Hospital, Liverpool, UK. 30. Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden. 31. Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA. 32. Child Health, University of Aberdeen, Aberdeen, UK. 33. Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain. 34. Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, San Cristóbal de La Laguna, Spain. 35. Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain mdelpino@ull.edu.es. 36. These authors contributed equally to this work.
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 children of European descent 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: 10 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.
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 children of European descent 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: 10 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.
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Authors: Victor E Ortega; Michelle Daya; Stanley J Szefler; Eugene R Bleecker; Vernon M Chinchilli; Wanda Phipatanakul; Dave Mauger; Fernando D Martinez; Esther Herrera-Luis; Maria Pino-Yanes; Gregory A Hawkins; Elizabeth J Ampleford; Susan J Kunselman; Corey Cox; Leonard B Bacharier; Michael D Cabana; Juan Carlos Cardet; Mario Castro; Loren C Denlinger; Celeste Eng; Anne M Fitzpatrick; Fernando Holguin; Donglei Hu; Daniel J Jackson; Nizar Jarjour; Monica Kraft; Jerry A Krishnan; Stephen C Lazarus; Robert F Lemanske; John J Lima; Njira Lugogo; Angel Mak; Wendy C Moore; Edward T Naureckas; Stephen P Peters; Jacqueline A Pongracic; Satria P Sajuthi; Max A Seibold; Lewis J Smith; Julian Solway; Christine A Sorkness; Sally Wenzel; Steven R White; Esteban G Burchard; Kathleen Barnes; Deborah A Meyers; Elliot Israel; Michael E Wechsler Journal: Lancet Child Adolesc Health Date: 2021-11-09
Authors: Mengyuan Kan; Avantika R Diwadkar; Haoyue Shuai; Jaehyun Joo; Alberta L Wang; Mei-Sing Ong; Joanne E Sordillo; Carlos Iribarren; Meng X Lu; Natalia Hernandez-Pacheco; Javier Perez-Garcia; Mario Gorenjak; Uroš Potočnik; Esteban G Burchard; Maria Pino-Yanes; Ann Chen Wu; Blanca E Himes Journal: J Allergy Clin Immunol Date: 2021-12-28 Impact factor: 14.290