TY - JOUR
T1 - ADRB2 Haplotypes and Asthma Exacerbations in Children and Young Adults
T2 - 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 - Verhamme, Katia M. C.
N1 - Funding - BREATHE was funded by Scottish Enterprises 343 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 r: 346 113201006). PAGES was funded by The Chief Scientist Office (reference number: CZH/4/418). 347 GALAII was funded by the National Heart, Lung, and Blood Institute of the National Institute of 348 Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported by the Sandler 349 Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty 350 Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical 351 Sciences II and the National Institute of Environmental Health Sciences grant R01ES015794. 352 SAGE was supported by the National Heart, Lung, and Blood Institute of the National Institute of 353 Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported by the Sandler 354 Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty 355 Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical 356 Sciences II. This study was also funded by the award (AC15/00015) funded by the Instituto de 357 Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European 358 Community (EC) within the Active and Assisted Living (AAL) Programme framework and the 359 SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European 360 Union under the Horizon 2020, and Maria Pino-Yanes was supported by the Ramón y Cajal 361 Program (RYC-2015-17205) by the Spanish Ministry of Economy, Industry, and Competitiveness. 362 Natalia Hernandez-Pacheco was supported by a fellowship (FI16/00136) from ISCIII and co-363 funded by the European Social Funds from the European Union (ESF) “ESF invests in your future. 364 PACMAN was supported by an unrestricted grant from GSK (part of a strategic alliance between 365 GSK and Utrecht Institute for Pharmaceutical Sciences (UIPS). PASS was funded by the UK 366 Department of Health through the NHS Chair of Pharmacogenomics and carried out at the 367 National Institute for Health Research (NIHR), Alder Hey Clinical Research Facility. In the 368 SLOVENIA study, the authors acknowledge the financial support from the Slovenian Research 369 Agency (research core funding No. P3-0067) and the SysPharmPedia grant, co-financed by the 370 Ministry of Education, Science and Sport of the Republic of Slovenia (contract number C3330-16-371 500106). Dr. CHEW Fook Tim (Singapore) received grants from the Singapore Ministry of 372 Education Academic Research Fund, Singapore Immunology Network, National Medical 373 Research Council (NMRC) (Singapore), and the Agency for Science Technology and Research 374 (A*STAR) (Singapore); Grant Numbers: N-154-000-038-001; R-154-000-191-112; R-154-000-375 404-112; R-154-000-553-112; R-154-000-565-112; R-154-000-630-112; R-154-000-A08-592; R-Accepted Article
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 ten independent studies (n = 5,903) of 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-analyzed 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 vs. Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2 = 0.0%) and Arg16/Gln27 vs. Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2 = 0.0%), but not Gly16/Gln27 vs. 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 i.e., as-required short-acting β2 -agonists (n = 973), ICS monotherapy (n = 2,623), 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 ten independent studies (n = 5,903) of 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-analyzed 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 vs. Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2 = 0.0%) and Arg16/Gln27 vs. Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2 = 0.0%), but not Gly16/Gln27 vs. 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 i.e., as-required short-acting β2 -agonists (n = 973), ICS monotherapy (n = 2,623), 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 - 10.1111/cea.13965
DO - 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 -