LTA4Hassociation with montelukast response in early and late-onset asthma

Leukotrienes play a central pathophysiological role in both pediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. To test 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 risk of experiencing asthma exacerbations in the G allele carriers’ group (AG or GG), despite montelukast treatment, was increased (odds-ratio=3.27, 95%confidence interval: 0.98–10.93, I2=69%, p=0.05) compared to those in the AA group. When meta-analyzing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR=1.69, 95% CI: 0.56-5.09, I2=84.81%, p=0.35).Our study demonstrates that genetic variation inLTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. Europeans individuals with early-onset (≤18y) carrying the rs2660845 G allele have increased risk 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.