Natalia Hernandez-Pacheco1,2, Niloufar Farzan3,4, Ben Francis5, Leila Karimi6, Katja Repnik7,8, Susanne J Vijverberg3,4, Patricia Soares9, Maximilian Schieck10,11, Mario Gorenjak7, Erick Forno12, Celeste Eng13, Sam S Oh13, Lina Pérez-Méndez14,15, Vojko Berce7,16, Roger Tavendale17, Lesly-Anne Samedy13,18, Scott Hunstman13, Donglei Hu13, Kelley Meade19, Harold J Farber20, Pedro C Avila21,22, Denise Serebrisky23, Shannon M Thyne24, Emerita Brigino-Buenaventura25, William Rodriguez-Cintron26, Saunak Sen27, Rajesh Kumar28,29, Michael Lenoir30, Jose R Rodriguez-Santana31, Juan C Celedón12, Somnath Mukhopadhyay9,17, Uroš Potočnik7,8, Munir Pirmohamed32, Katia M Verhamme6, Michael Kabesch10, Colin N A Palmer17, Daniel B Hawcutt5,33, Carlos Flores1,15,34, Anke H Maitland-van der Zee3,4,35, Esteban G Burchard13,18, Maria Pino-Yanes1,2,15. 1. Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, San Cristóbal de La Laguna, Spain. 2. Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain. 3. Department of Respiratory Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands. 4. Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Utrecht, Netherlands. 5. Department of Women's and Children's Health, University of Liverpool, Liverpool, UK. 6. Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands. 7. Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Maribor, Slovenia. 8. Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia. 9. Academic Department of Paediatrics, Brighton and Sussex Medical School, Royal Alexandra Children's Hospital, Brighton, UK. 10. Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany. 11. Department of Human Genetics, Hannover Medical School, Hannover, Germany. 12. Division of Pediatric Pulmonary Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh, Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania. 13. Department of Medicine, University of California, San Francisco, California. 14. Department of Clinic Epidemiology and Biostatistics, Research Unit, Hospital Universitario N.S. de Candelaria, Gerencia de Atención Primaria, Santa Cruz de Tenerife, Spain. 15. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 16. Department of Pediatrics, University Medical Centre Maribor, Maribor, Slovenia. 17. Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. 18. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California. 19. Children's Hospital and Research Center Oakland, Oakland, California. 20. Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas. 21. Department of Medicine, Northwestern University, Chicago, Illinois. 22. Allergy & ENT Associates, The Woodland, Texas. 23. Pediatric Pulmonary Division, New York, NY. 24. Department of Pediatrics, University of California, San Francisco, California. 25. Department of Allergy and Immunology, Vallejo, California. 26. Veterans Caribbean Health Care System, San Juan, Puerto Rico. 27. University of Tennessee Health Science Center, Memphis, Tennessee. 28. Feinberg School of Medicine's Division of Allergy and Immunology, Northwestern University, Chicago, Illinois. 29. Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. 30. Bay Area Pediatrics, Oakland, California. 31. Centro de Neumología Pediátrica, San Juan, Puerto Rico. 32. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 33. Alder Hey Children's Hospital, Liverpool, UK. 34. Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain. 35. Department of Pediatric Respiratory Medicine and Allergy, Emma's Children Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
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.
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 asthmapatients who are not able to respond to such treatment.
Authors: Belete A Desimmie; Krista A Delviks-Frankenberrry; Ryan C Burdick; DongFei Qi; Taisuke Izumi; Vinay K Pathak Journal: J Mol Biol Date: 2013-11-02 Impact factor: 5.469
Authors: Ann Chen Wu; Blanca E Himes; Jessica Lasky-Su; Augusto Litonjua; Stephen P Peters; John Lima; Michiaki Kubo; Mayumi Tamari; Yusuke Nakamura; Weiliang Qiu; Scott T Weiss; Kelan Tantisira Journal: J Allergy Clin Immunol Date: 2013-11-23 Impact factor: 10.793
Authors: Marquitta J White; O Risse-Adams; P Goddard; M G Contreras; J Adams; D Hu; C Eng; S S Oh; A Davis; K Meade; E Brigino-Buenaventura; M A LeNoir; K Bibbins-Domingo; M Pino-Yanes; E G Burchard Journal: Immunogenetics Date: 2016-05-03 Impact factor: 2.846
Authors: Maria Pino-Yanes; Neeta Thakur; Christopher R Gignoux; Joshua M Galanter; Lindsey A Roth; Celeste Eng; Katherine K Nishimura; Sam S Oh; Hita Vora; Scott Huntsman; Elizabeth A Nguyen; Donglei Hu; Katherine A Drake; David V Conti; Andres Moreno-Estrada; Karla Sandoval; Cheryl A Winkler; Luisa N Borrell; Fred Lurmann; Talat S Islam; Adam Davis; Harold J Farber; Kelley Meade; Pedro C Avila; Denise Serebrisky; Kirsten Bibbins-Domingo; Michael A Lenoir; Jean G Ford; Emerita Brigino-Buenaventura; William Rodriguez-Cintron; Shannon M Thyne; Saunak Sen; Jose R Rodriguez-Santana; Carlos D Bustamante; L Keoki Williams; Frank D Gilliland; W James Gauderman; Rajesh Kumar; Dara G Torgerson; Esteban G Burchard Journal: J Allergy Clin Immunol Date: 2014-10-06 Impact factor: 10.793
Authors: Liv B Gansmo; Paal Romundstad; Kristian Hveem; Lars Vatten; Serena Nik-Zainal; Per Eystein Lønning; Stian Knappskog Journal: Carcinogenesis Date: 2018-02-09 Impact factor: 4.944
Authors: Jasmien Roosenboom; Myoung Keun Lee; Jacqueline T Hecht; Carrie L Heike; George L Wehby; Kaare Christensen; Eleanor Feingold; Mary L Marazita; A Murat Maga; John R Shaffer; Seth M Weinberg Journal: PLoS One Date: 2018-04-26 Impact factor: 3.240
Authors: Eunice Y Lee; Angel C Y Mak; Donglei Hu; Satria Sajuthi; Marquitta J White; Kevin L Keys; Walter Eckalbar; Luke Bonser; Scott Huntsman; Cydney Urbanek; Celeste Eng; Deepti Jain; Gonçalo Abecasis; Hyun M Kang; Soren Germer; Michael C Zody; Deborah A Nickerson; David Erle; Elad Ziv; Jose Rodriguez-Santana; Max A Seibold; Esteban G Burchard Journal: Am J Respir Crit Care Med Date: 2020-10-01 Impact factor: 21.405
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: Natalia Hernandez-Pacheco; Mario Gorenjak; Staša Jurgec; Almudena Corrales; Andrea Jorgensen; Leila Karimi; Susanne J Vijverberg; Vojko Berce; Maximilian Schieck; Marialbert Acosta-Herrera; Martin Kerick; Lesly-Anne Samedy-Bates; Roger Tavendale; Jesús Villar; Somnath Mukhopadhyay; Munir Pirmohamed; Katia M C Verhamme; Michael Kabesch; Daniel B Hawcutt; Steve Turner; Colin N Palmer; Esteban G Burchard; Anke H Maitland-van der Zee; Carlos Flores; Uroš Potočnik; Maria Pino-Yanes Journal: Allergy Date: 2020-09-16 Impact factor: 13.146
Authors: Natalia Hernandez-Pacheco; Susanne J Vijverberg; Esther Herrera-Luis; Jiang Li; Yang Yie Sio; Raquel Granell; Almudena Corrales; Cyrielle Maroteau; Ryan Lethem; Javier Perez-Garcia; Niloufar Farzan; Katja Repnik; Mario Gorenjak; Patricia Soares; Leila Karimi; Maximilian Schieck; Lina Pérez-Méndez; Vojko Berce; Roger Tavendale; Celeste Eng; Olaia Sardon; Inger Kull; Somnath Mukhopadhyay; Munir Pirmohamed; Katia M C Verhamme; Esteban G Burchard; Michael Kabesch; Daniel B Hawcutt; Erik Melén; Uroš Potočnik; Fook Tim Chew; Kelan G Tantisira; Steve Turner; Colin N Palmer; Carlos Flores; Maria Pino-Yanes; Anke H Maitland-van der Zee Journal: Eur Respir J Date: 2021-05-13 Impact factor: 16.671
Authors: Yiwei Liu; Wenjian Yang; Colton A Smith; Cheng Cheng; Seth E Karol; Eric C Larsen; Naomi Winick; William L Carroll; Mignon L Loh; Elizabeth A Raetz; Stephen P Hunger; Stuart S Winter; Kimberly P Dunsmore; Meenakshi Devidas; Jun J Yang; William E Evans; Sima Jeha; Ching-Hon Pui; Hiroto Inaba; Mary V Relling Journal: Clin Pharmacol Ther Date: 2021-04-21 Impact factor: 6.903
Authors: Leila Karimi; Susanne J Vijverberg; Marjolein Engelkes; Natalia Hernandez-Pacheco; Niloufar Farzan; Patricia Soares; Maria Pino-Yanes; Andrea L Jorgensen; Celeste Eng; Somnath Mukhopadhyay; Maximilian Schieck; Michael Kabesch; Esteban G Burchard; Fook Tim Chew; Yang Yie Sio; Uroš Potočnik; Mario Gorenjak; Daniel B Hawcutt; Colin N Palmer; Steve Turner; Hettie M Janssens; Anke H Maitland-van der Zee; Katia M C Verhamme Journal: Clin Exp Allergy Date: 2021-07-20 Impact factor: 5.401