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LTA4H rs2660845 association with montelukast response in early and late-onset asthma

Authors :
Glenda Lassi
Maria Pino-Yanes
Somnath Mukhopadhyay
Roger Tavendale
Antonio Espuela-Ortiz
Karen Wilson
Natalia Hernandez-Pacheco
Colin N. A. Palmer
Simon Young
Steve Turner
Adam Platt
Cyrielle Maroteau
Fiona Carr
Esteban G. Burchard
Anke-Hilse Maitland-van der Zee
Esther Herrera-Luis
James D. Chalmers
Sundararajan Srinivasan
Pulmonology
Paediatric Pulmonology
AII - Inflammatory diseases
APH - Personalized Medicine
Source :
PLoS ONE, 16(9 September):e0257396. Public Library of Science, PLoS ONE, PLoS ONE, Vol 16, Iss 9, p e0257396 (2021)
Publication Year :
2021
Publisher :
Public Library of Science, 2021.

Abstract

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of theLTA4Hregulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04–8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61–4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation inLTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation ofLTA4Hactivity. These findings support a precision medicine approach for the treatment of asthma with montelukast.

Details

Language :
English
ISSN :
19326203
Database :
OpenAIRE
Journal :
PLoS ONE, 16(9 September):e0257396. Public Library of Science, PLoS ONE, PLoS ONE, Vol 16, Iss 9, p e0257396 (2021)
Accession number :
edsair.doi.dedup.....e583b11172691656d2a829454145a0c7