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

Cyrielle Maroteau (Lead / Corresponding author), Antonio Espuela-Ortiz, Esther Herrera-Luis, Sundararajan Srinivasan, Fiona Carr, Roger Tavendale, Karen Wilson, Natalia Hernandez-Pacheco, James D. Chalmers, Steve Turner, Somnath Mukhopadhyay, Anke Hilse Maitland-Van der Zee, Esteban G. Burchard, Maria Pino-Yanes, Simon Young, Glenda Lassi, Adam Platt, Colin N. A. Palmer,

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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 the LTA4H regulatory 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 in LTA4H, 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 of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.

Original languageEnglish
Article numbere0257396
Number of pages17
JournalPLoS ONE
Volume16
Issue number9
DOIs
Publication statusPublished - 22 Sep 2021

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