Sze Man Tse1,2, Maja Krajinovic2, Bhupendrasinh F Chauhan3,4, Roger Zemek5,6, Jocelyn Gravel1,2, Dominic Chalut7, Naveen Poonai8, Caroline Quach2,9, Sophie Laberge1,2, Francine M Ducharme1,2,10. 1. Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada. 2. Research Centre, Sainte-Justine University Health Centre, Montreal, Quebec, Canada. 3. Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada. 4. Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada. 5. Department of Pediatrics and Emergency Medicine, University of Ottawa, Ontario, Canada. 6. Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada. 7. Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada. 8. Children's Hospital, London Health Sciences Center, London, Ontario, Canada. 9. Department of Microbiology, Infectious Diseases, and Immunology, University of Montreal, Montreal, Quebec, Canada. 10. Department of Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada.
Abstract
BACKGROUND: We documented inter-individual variability in the response to acute asthma therapy in children, attributed in part to five clinical factors (oxygen saturation, asthma severity score, virus detection, fever, symptoms between exacerbations; DOORWAY study). The contribution of genetic determinants of failure of acute asthma management have not been elucidated. OBJECTIVE: We aim to determine single nucleotide polymorphisms (SNP) associated with emergency department (ED) management failure in children. METHODS: A prospective cohort of 591 Caucasian children aged 1-17 years with moderate-to-severe asthma managed with standardized protocol were included. We examined 53 SNPs previously associated with asthma development, phenotypes, or bronchodilator or corticosteroids response. Associations between SNPs and management failure (hospitalization, active asthma management ≥8 h in ED, or a return visit within 72 h for one of two previous criteria) were examined using logistic regression, adjusting for the five clinical predictors of management failure. RESULTS: Four-hundred ninety-one subjects had complete clinical data and usable DNA samples. While controlling for clinical determinants, rs295137 in SPATS2L (OR = 1.77, 95%CI: 1.17, 2.68) was significantly associated with increased odds of ED management failure. Two SNPs in IL33 were associated with decreased odds of ED management failure: rs7037276 (OR = 0.55, 95%CI: 0.33, 0.90), and rs1342326 (OR = 0.52, 95%CI: 0.32, 0.86). The addition of these three SNPs to the clinical predictors significantly improved the model's predictive performance (P < 0.0004). CONCLUSION: Three SNPs were significantly associated with ED management failure in addition to clinical predictors, contributing to inter-individual variability. None has been previously associated with treatment response to acute asthma management.
BACKGROUND: We documented inter-individual variability in the response to acute asthma therapy in children, attributed in part to five clinical factors (oxygen saturation, asthma severity score, virus detection, fever, symptoms between exacerbations; DOORWAY study). The contribution of genetic determinants of failure of acute asthma management have not been elucidated. OBJECTIVE: We aim to determine single nucleotide polymorphisms (SNP) associated with emergency department (ED) management failure in children. METHODS: A prospective cohort of 591 Caucasian children aged 1-17 years with moderate-to-severe asthma managed with standardized protocol were included. We examined 53 SNPs previously associated with asthma development, phenotypes, or bronchodilator or corticosteroids response. Associations between SNPs and management failure (hospitalization, active asthma management ≥8 h in ED, or a return visit within 72 h for one of two previous criteria) were examined using logistic regression, adjusting for the five clinical predictors of management failure. RESULTS: Four-hundred ninety-one subjects had complete clinical data and usable DNA samples. While controlling for clinical determinants, rs295137 in SPATS2L (OR = 1.77, 95%CI: 1.17, 2.68) was significantly associated with increased odds of ED management failure. Two SNPs in IL33 were associated with decreased odds of ED management failure: rs7037276 (OR = 0.55, 95%CI: 0.33, 0.90), and rs1342326 (OR = 0.52, 95%CI: 0.32, 0.86). The addition of these three SNPs to the clinical predictors significantly improved the model's predictive performance (P < 0.0004). CONCLUSION: Three SNPs were significantly associated with ED management failure in addition to clinical predictors, contributing to inter-individual variability. None has been previously associated with treatment response to acute asthma management.
Authors: Alexander G Mathioudakis; Michael Miligkos; Cristina Boccabella; Gioulinta S Alimani; Adnan Custovic; A Deschildre; Francine Monique Ducharme; Omer Kalayci; Clare Murray; Antonio Nieto Garcia; Wanda Phipatanakul; David Price; Aziz Sheikh; Ioana Octavia Agache; Leonard Bacharier; Apostolos Beloukas; Andrew Bentley; Matteo Bonini; Jose A Castro-Rodriguez; Giuseppe De Carlo; Timothy Craig; Zuzana Diamant; Wojciech Feleszko; Tim Felton; James E Gern; Jonathan Grigg; Gunilla Hedlin; Elham M Hossny; Despo Ierodiakonou; Tuomas Jartti; Alan Kaplan; Robert F Lemanske; Peter N Le Souëf; Mika J Mäkelä; Georgios A Mathioudakis; Paolo Matricardi; Marina Mitrogiorgou; Mario Morais-Almeida; Karthik Nagaraju; Effie Papageorgiou; Helena Pité; Paulo M C Pitrez; Petr Pohunek; Graham Roberts; Ioanna Tsiligianni; Stephen Turner; Susanne Vijverberg; Tonya A Winders; Gary Wk Wong; Paraskevi Xepapadaki; Heather J Zar; Nikolaos G Papadopoulos Journal: BMJ Open Date: 2021-07-02 Impact factor: 2.692