Victor E Ortega1, Michelle Daya2, Stanley J Szefler3, Eugene R Bleecker4, Vernon M Chinchilli5, Wanda Phipatanakul6, Dave Mauger5, Fernando D Martinez7, Esther Herrera-Luis8, Maria Pino-Yanes9, Gregory A Hawkins10, Elizabeth J Ampleford11, Susan J Kunselman5, Corey Cox2, Leonard B Bacharier12, Michael D Cabana13, Juan Carlos Cardet14, Mario Castro15, Loren C Denlinger16, Celeste Eng17, Anne M Fitzpatrick18, Fernando Holguin2, Donglei Hu17, Daniel J Jackson19, Nizar Jarjour16, Monica Kraft4, Jerry A Krishnan20, Stephen C Lazarus17, Robert F Lemanske19, John J Lima21, Njira Lugogo22, Angel Mak17, Wendy C Moore11, Edward T Naureckas23, Stephen P Peters11, Jacqueline A Pongracic24, Satria P Sajuthi25, Max A Seibold26, Lewis J Smith27, Julian Solway23, Christine A Sorkness16, Sally Wenzel28, Steven R White23, Esteban G Burchard17, Kathleen Barnes2, Deborah A Meyers4, Elliot Israel29, Michael E Wechsler30. 1. Department of Internal Medicine, Section for Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address: ortega.victor@mayo.edu. 2. Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA. 3. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, CO, USA. 4. Department of Internal Medicine, Division of Genetics, Genomics, and Precision Medicine, University of Arizona College of Medicine, Tucson, AZ, USA. 5. Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA. 6. Division of Pediatric Allergy and Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 7. Asthma and Airway Disease Research Center, University of Arizona Health Sciences, Tucson, AZ, USA. 8. Department of Biochemistry, La Laguna, Tenerife, Spain; Microbiology, Cell Biology, and Genetics, La Laguna, Tenerife, Spain; Genomics and Health Group, La Laguna, Tenerife, Spain; Universidad de La Laguna, La Laguna, Tenerife, Spain. 9. Department of Biochemistry, La Laguna, Tenerife, Spain; Microbiology, Cell Biology, and Genetics, La Laguna, Tenerife, Spain; Genomics and Health Group, La Laguna, Tenerife, Spain; Universidad de La Laguna, La Laguna, Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 10. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. 11. Department of Internal Medicine, Section for Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA. 12. Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA. 13. Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA. 14. Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. 15. Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kansas Medical Center, Kansas City, KS, USA. 16. Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin-Madison, Madison, WI, USA. 17. Department of Medicine, University of California San Francisco, San Francisco, CA, USA. 18. Department of Pediatrics, Emory University, Atlanta, GA, USA. 19. Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, USA. 20. Breathe Chicago Center, Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois, Chicago, IL, USA. 21. Center for Pharmacogenomics and Translational Research, Nemours Children's Health System, Jacksonville, FL, USA. 22. Department of Medicine, Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA. 23. Department of Medicine, University of Chicago, Chicago, IL, USA. 24. Department of Pediatrics, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA. 25. Center for Genes, Environment, and Health, Department of Pediatrics, National Jewish Health, Denver, CO, USA. 26. Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA; Center for Genes, Environment, and Health, Department of Pediatrics, National Jewish Health, Denver, CO, USA. 27. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 28. Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 29. Department of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 30. Department of Medicine, National Jewish Health, Denver, CO, USA.
Abstract
BACKGROUND: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. FINDINGS: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. INTERPRETATION: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. FUNDING: National Institutes of Health, National Heart, Lung, and Blood Institute.
BACKGROUND: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. FINDINGS: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. INTERPRETATION: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. FUNDING: National Institutes of Health, National Heart, Lung, and Blood Institute.
Authors: Katherine A Drake; Dara G Torgerson; Christopher R Gignoux; Joshua M Galanter; Lindsey A Roth; Scott Huntsman; Celeste Eng; Sam S Oh; Sook Wah Yee; Lawrence Lin; Carlos D Bustamante; Andrés Moreno-Estrada; Karla Sandoval; Adam Davis; Luisa N Borrell; Harold J Farber; Rajesh Kumar; Pedro C Avila; Emerita Brigino-Buenaventura; Rocio Chapela; Jean G Ford; Michael A Lenoir; Fred Lurmann; Kelley Meade; Denise Serebrisky; Shannon Thyne; William Rodríguez-Cintrón; Saunak Sen; José R Rodríguez-Santana; Ryan D Hernandez; Kathleen M Giacomini; Esteban G Burchard Journal: J Allergy Clin Immunol Date: 2013-08-29 Impact factor: 10.793
Authors: Rafal S Sobota; Daniel Shriner; Nuri Kodaman; Robert Goodloe; Wei Zheng; Yu-Tang Gao; Todd L Edwards; Christopher I Amos; Scott M Williams Journal: Ann Hum Genet Date: 2015-01-22 Impact factor: 1.670
Authors: William W Busse; Eric D Bateman; Arthur L Caplan; H William Kelly; Paul M O'Byrne; Klaus F Rabe; Vernon M Chinchilli Journal: N Engl J Med Date: 2018-06-28 Impact factor: 91.245
Authors: M E Wechsler; H Grasemann; A Deykin; E K Silverman; C N Yandava; E Israel; M Wand; J M Drazen Journal: Am J Respir Crit Care Med Date: 2000-12 Impact factor: 21.405
Authors: S J Szefler; H A Boushey; D S Pearlman; A Togias; R Liddle; A Furlong; T Shah; K Knobil Journal: J Allergy Clin Immunol Date: 1999-05 Impact factor: 10.793
Authors: Corinne A Keet; Meredith C McCormack; Craig E Pollack; Roger D Peng; Emily McGowan; Elizabeth C Matsui Journal: J Allergy Clin Immunol Date: 2015-01-20 Impact factor: 10.793
Authors: Lieza M Danan; Zhihao Yu; Adam J Hoffhines; Kevin L Moore; Julie A Leary Journal: J Am Soc Mass Spectrom Date: 2008-07-01 Impact factor: 3.109