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

Centre for Genomics Research, Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom. Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, United Kingdom. Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, San Cristobal de La Laguna, Santa Cruz de Tenerife, Spain. Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, San Cristobal de La Laguna, Spain. Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom. Child Health, University of Aberdeen, Aberdeen, United Kingdom. Academic Department of Pediatrics, Brighton and Sussex Medical School, Royal Alexandra Children's Hospital, Brighton, United Kingdom. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands. Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Department of Pediatric Respiratory Medicine and Allergy, Emma's Children Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands. Department of Medicine, University of California San Francisco, San Francisco, California, United States of America. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain. Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain. BioPharmaceutical Precision Medicine, Oncology R&D, AstraZeneca, Cambridge, United Kingdom. Research & Development Centre, Sysmex, Cambridge, United Kingdom. Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.

PloS one. 2021;(9):e0257396
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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.