Abstract
Original language | English |
---|---|
Pages (from-to) | 1157-1171 |
Number of pages | 15 |
Journal | Clinical and experimental allergy |
Volume | 51 |
Issue number | 9 |
Early online date | 2021 |
DOIs | |
Publication status | Published - Sept 2021 |
Keywords
- ADRB2
- asthma exacerbations
- haplotypes
- inhaled corticosteroids
- long-acting β -agonists
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In: Clinical and experimental allergy, Vol. 51, No. 9, 09.2021, p. 1157-1171.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta-analysis
AU - Karimi, Leila
AU - Vijverberg, Susanne J.
AU - Engelkes, Marjolein
AU - Hernandez-Pacheco, Natalia
AU - Farzan, Niloufar
AU - Soares, Patricia
AU - Pino-Yanes, Maria
AU - Jorgensen, Andrea L.
AU - Eng, Celeste
AU - Mukhopadhyay, Somnath
AU - Schieck, Maximilian
AU - Kabesch, Michael
AU - Burchard, Esteban G.
AU - Chew, Fook Tim
AU - Sio, Yang Yie
AU - Potočnik, Uroš
AU - Gorenjak, Mario
AU - Hawcutt, Daniel B.
AU - Palmer, Colin N.
AU - Turner, Steve
AU - Janssens, Hettie M.
AU - Maitland-van der Zee, Anke H.
AU - On behalf of the PiCA and SysPharmPedia consortia
AU - Verhamme, Katia M. C.
N1 - Funding Information: The authors gratefully acknowledge the dedication, commitment and contribution of the patients, families, recruiters, health care providers and pharmacists participating in all the studies involved in the PiCA consortium. In particular, the authors thank Sandra Salazar for her support as the GALA II / SAGE study coordinator. Individual cohorts were funded as follows: BREATHE was funded by Scottish Enterprises Tayside, the Gannochy Trust, and the Perth and Kinross Council, and Brighton and Sussex Medical School. ESTATe was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw; priority for medicines for children, Grant/Award Number: 113201006). PAGES was funded by The Chief Scientist Office (reference number: CZH/4/418). GALAII 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 and the National Institute of Environmental Health Sciences grant R01ES015794. SAGE 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. This study was also funded by the award (AC15/00015) 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 and the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020, and Maria Pino‐Yanes was supported by the Ramón y Cajal Program (RYC‐2015‐17205) by the Spanish Ministry of Economy, Industry, and Competitiveness. Natalia Hernandez‐Pacheco was supported by a fellowship (FI16/00136) from ISCIII and co‐funded by the European Social Funds from the European Union (ESF) “ESF invests in your future. PACMAN was supported by an unrestricted grant from GSK (part of a strategic alliance between GSK and Utrecht Institute for Pharmaceutical Sciences (UIPS)). PASS was funded by the UK Department of Health through the NHS Chair of Pharmacogenomics and carried out at the National Institute for Health Research (NIHR), Alder Hey Clinical Research Facility. In the SLOVENIA study, the authors acknowledge the financial support from the Slovenian Research Agency (research core funding No. P3‐0067) and the SysPharmPedia grant, co‐financed by the Ministry of Education, Science and Sport of the Republic of Slovenia (contract number C3330‐16‐500106). Dr. CHEW Fook Tim (Singapore) received grants from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore); Grant Numbers: N‐154‐000‐038‐001; R‐154‐000‐191‐112; R‐154‐000‐404‐112; R‐154‐000‐553‐112; R‐154‐000‐565‐112; R‐154‐000‐630‐112; R‐154‐000‐A08‐592; R‐154‐000‐A27‐597; R‐154‐000‐A91‐592; R‐154‐000‐A95‐592; R154‐000‐B99‐114; BMRC/01/1/21/18/077; BMRC/04/1/21/19/315; SIgN‐06‐006; SIgN‐08‐020; NMRC/1150/2008; H17/01/a0/008; and APG2013/108. FollwMAGICS was founded by the German charity Atemwegsliga and the German Ministry of Science and Education, grant Sysinflame (grant number 01ZX1306E). Funding Information: Dr. Maitland‐van der Zee reports personal fees for participating in advisory boards from Astra Zeneca, Boehringer Ingelheim, unrestricted research grants from Boehringer Ingelheim, and GlaxoSmithKline (GSK). Dr. Vijverberg has received a grant from GSK during the conduct of the study. Dr. Pino‐Yanes reports grants and non‐financial support from the Spanish Ministry of Economy and Competitiveness, and Instituto de Salud Carlos III (ISCIII); during the conduct of the study. Dr. CHEW reports grants from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore), during the conduct of the study; consultancy fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work. Dr. Janssens reports grants from Vectura and personal fees from Vertex, outside the submitted work. Dr. Katia Verhamme reports grants from ZonMw, during the conduct of the study; and KV works for a research group who receives/received unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis, and GSK; outside the submitted work. Dr. Engelkes reports grants from ZonMw, during the conduct of the study. Dr. Kabesch reports that his institution received a grant from European Union, German Ministry of Education and Research, German Research Foundation, and received personal fees from consultancy and for participating in advisory boards from Bionorica, Sanofi, Novartis, Bencard, European respiratory society (ERS), European Academy of Allergy and Clinical Immunology (EAACI), American Thoracic Society (ATS), Novartis, Glaxo, Nutricia, Hipp; Allergopharma, and Teva; outside the submitted work. Hernandez‐Pacheco reports grants from Instituto de Salud Carlos III (ISCIII) during the conduct of the study. Dr. Farzan is currently working at Breathomix BV, Leiden, The Netherlands, outside the submitted work. Leila Karimi MD is currently working at IQVIA, The Netherlnads, outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: © 2021 John Wiley & Sons Ltd
PY - 2021/9
Y1 - 2021/9
N2 - Background: The polymorphism Arg16 in β2-adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β2-agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. Results: In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β2-agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.
AB - Background: The polymorphism Arg16 in β2-adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β2-agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. Results: In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β2-agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.
KW - ADRB2
KW - asthma exacerbations
KW - haplotypes
KW - inhaled corticosteroids
KW - long-acting β -agonists
UR - http://www.scopus.com/inward/record.url?scp=85110966202&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/cea.13965
DO - https://doi.org/10.1111/cea.13965
M3 - Article
C2 - 34128573
SN - 0954-7894
VL - 51
SP - 1157
EP - 1171
JO - Clinical and experimental allergy
JF - Clinical and experimental allergy
IS - 9
ER -