. 2021 Dec;5(12):862-872.

doi: 10.1016/S2352-4642(21)00268-6. Epub 2021 Nov 9.

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma

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 Lemanske Jr¹⁹, 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; NHLBI AsthmaNet

Collaborators, Affiliations

Affiliations

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.

PMID: 34762840
PMCID: PMC8787857
DOI: 10.1016/S2352-4642(21)00268-6

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma

Victor E Ortega et al. Lancet Child Adolesc Health. 2021 Dec.

. 2021 Dec;5(12):862-872.

doi: 10.1016/S2352-4642(21)00268-6. Epub 2021 Nov 9.

Authors

Affiliations

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.

PMID: 34762840
PMCID: PMC8787857
DOI: 10.1016/S2352-4642(21)00268-6

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 [OR_{local 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, OR_{allele 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 (OR_{local African} 3·35, 1·98-5·67, p=6·8 × 10^-6) containing a locus adjacent to TPST2 (rs5752429, OR_{allele 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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests VEO reports consulting fees from Sanofi and fees for serving on independent data monitoring committees for Sanofi and Regeneron Pharmaceuticals. SJS reports receiving consulting fees, paid to his institution, from AstraZeneca, GlaxoSmithKline, Moderna, Propeller Health, Regeneron, and Sanofi, as well as a research grant from Propeller Health. ERB reports receiving consulting fees and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, consulting fees from AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, and Sanofi–Regeneron, and participating in trials as an employee of Wake Forest School of Medicine and the University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Cephalon–Teva Pharmaceuticals, Genentech, GlaxoSmithKline, Johnson & Johnson (Janssen), Novartis, and Sanofi–Regeneron. VMC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. WP reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DM reports receiving grant support and donated drugs from GlaxoSmithKline, Genentech, Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, fees for serving on a data and safety monitoring board from Novartis, and donated drugs from Merck. FDM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support from Johnson & Johnson, and consulting fees from Copeval and Commence. EH-L reports a fellowship from the Spanish Ministry of Science, Innovation, and Universities. MP-Y reports grants from the Spanish Ministry of Economy, Industry, and Competitiveness, the State Research Agency and the European Regional Development Funds from the European Union (MICIU/AEI/FEDER, UE), and grant support from GlaxoSmithKline, Spain. SJK reports receiving donated drugs from Merck–Organon, Genentech, GlaxoSmithKline, and Regeneron and owning stock in Merck. LBB reports receiving consulting fees and lecture fees from Aerocrine, GlaxoSmithKline, Genentech–Novartis, and AstraZeneca, advisory board fees and donated drugs from Merck, fees for serving on a data safety monitoring board from DBV Technologies, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals and Boehringer Ingelheim, honoraria from WebMD–Medscape, advisory board fees and lecture fees from Sanofi–Regeneron, advisory board fees and consulting fees from Vectura, and advisory board fees from Circassia. MDC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and consulting fees from Genentech and Novartis. JCC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. MC reports receiving grant support, lecture fees, and donated drugs from Boehringer Ingelheim, donated drugs from Merck, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals, consulting fees and lecture fees from Boston Scientific and Genentech, consulting fees from Nuvaira, Aviragen, 4D Pharma, VIDA Diagnostics, Mallinckrodt Pharmaceuticals, Theravance, Therabron, and Vectura, grant support, consulting fees, and lecture fees from Sanofi-Aventis, grant support and lecture fees from AstraZeneca and GlaxoSmithKline, grant support from Chiesi and Novartis, and lecture fees from Regeneron Pharmaceuticals. LCD reports receiving grant support and consulting fees from AstraZeneca, and consulting fees from Sanofi–Regeneron. FH reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DJJ reports grant support from GlaxoSmithKline, consulting fees from Novartis, Sanofi, Regeneron, Vifor Pharma, and AstraZeneca, and fees for serving on a data and safety monitoring board from Pfizer. NJ reports receiving honorarium for consulting from GlaxoSmithKline pharmaceuticals and Pulmocide. MK reports receiving grant support from Chiesi and Sanofi. JAK reports personal fees for independent data monitoring committee participation from Sanofi and research funding from the American Lung Association—Airway Clinical Research Centers Network. SCL reports grant funding from the American Lung Association—Airway Clinical Research Centers Network. RFL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and lecture fees from Thermo Fisher Scientific. JJL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. NL reports receiving grant support, advisory board fees, and donated drugs from GlaxoSmithKline, grant support, consulting fees, and advisory board fees from AstraZeneca, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, grant support from Genentech, grant support and advisory board fees from Sanofi–Regeneron, and donated drugs from Merck and Boehringer Ingelheim. WCM reports receiving grant support and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, grant support and advisory board fees from AstraZeneca, GlaxoSmithKline, and Sanofi–Regeneron, and grant support from Novartis, Cumberland Pharmaceuticals, and Gossamer Bio. SPP reports receiving advisory board fees from AstraZeneca, GlaxoSmithKline, Mylan, Teva Pharmaceuticals, Sanofi–Regeneron, and Theravance, fees for serving as clinical trial adjudicator from Quintiles, fees for serving on a data and safety monitoring board from Genentech, fees for serving as chair of a data and safety monitoring board from Novartis, and honoraria from PRIME. JAP reports receiving donated drugs from Boehringer Ingelheim, Merck, Teva Pharmaceuticals, and GlaxoSmithKline. LJS reports receiving donated drugs from Boehringer Ingelheim and Teva Pharmaceuticals, and fees for serving on a data and safety monitoring board and donated drugs from Merck. JS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, advisory board fees from PulmOne Advanced Medical Devices, advisory board fees, honoraria, and travel support from Regeneron–Sanofi–Genzyme, holding patents #6 090 618, #6 114 311, #6 284 743, #6 291 211, #6 297 221, #6 331 527, and #7 169 764 on a smooth-muscle gene promoter (SM22 alpha), holding pending patent PCT/US2014/032186 on a method for determining respiratory physiological parameters, holding pending patent 62/872,980 on remodilins for airway remodelling and organ fibrosis, and holding pending patent 62/828,122 on remodilins to prevent or treat cancer metastasis, glaucoma, and hypoxia. CAS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. SW reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support and consulting fees from AstraZeneca and Sanofi, and consulting fees from Pieris Pharmaceuticals. DAM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. EI reports receiving grant support and consulting fees from AstraZeneca, Novartis, and Genentech, consulting fees from Regeneron Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi Genzyme, Entrinsic Health Solutions, Pneuma Respiratory, 4D Pharma, Sienna Biopharmaceuticals, and Equillium, grant support, consulting fees, and donated drugs from Merck, Teva Pharmaceutical Industries, and GlaxoSmithKline, serving as a consultant for Vorso, receiving grant support and donated drugs from Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, and donated drugs from Circassia. MEW reports receiving grant support and consulting fees from AstraZeneca, Novartis, Sanofi, and GlaxoSmithKline, consulting fees from Regeneron Pharmaceuticals, Mylan, Genentech, Restorbio, Equillium, Boston Scientific, Genzyme, Gala Therapeutics, and Pulmatrix, fees for serving on a data and safety monitoring board from Sentien Biotechnologies, grant support, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, consulting fees and donated drugs from Boehringer Ingelheim and Merck. MD, GAH, EJA CC, CE, AMF, DH, AM, ETN, SPS, MAS, SRW, EGB, and KB declare no competing interests.

Figures

**Figure 1:. BARD Pharmacogenetic Study Flow Diagram.**
This flow diagram summarizes the sequential analytical steps of the pharmacogenetic studies of the BARD four-arm cross-over trials in children and in adolescent and adult groups. The first series of studies was whole-genome admixture mapping to identifying ancestral chromosomal segments having genome-wide significant associations (p_{local African}<1.6x10⁻⁴ based on 15,159 ancestral segments within 312 independent regions) for superior response to the co-primary treatment arm comparisons of (1) quintupling inhaled corticosteroid dose (5xICS) versus doubling corticosteroid dose (2–2.5xICS) and (2) 5xICS versus the addition of LABA to low-dose ICS (FP100SAL). Second, we performed fine mapping of the ancestral segments reaching genome-wide significance in each age group to identify individual variants using Local Ancestry Adjusted Allelic Association (LAAA) models. Finally, we evaluated each of the top SNP allelic associations (p_{allele dose}<10⁻³) for replication in independent African American and Puerto Rican adolescents and children (SAGE and GALA II) and an African American Adolescent and Adult (AAAA) clinical trial cohort.

See this image and copyright information in PMC

Comment in

Towards diversity in asthma pharmacogenetics.
Kersten ETG, Koppelman GH. Kersten ETG, et al. Lancet Child Adolesc Health. 2021 Dec;5(12):838-839. doi: 10.1016/S2352-4642(21)00330-8. Epub 2021 Nov 9. Lancet Child Adolesc Health. 2021. PMID: 34762839 No abstract available.

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Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma

Collaborators

Affiliations

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical