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

Cyrielle Maroteau,Simon Young,Glenda Lassi,Roger Tavendale,Sundararajan Srinivasan,James D Chalmers,Somnath Mukhopadhyay,Esteban G Burchard,Fiona Carr,Karen Wilson,Adam Platt,Antonio Espuela‐Ortiz ,Natalia Hernandez‐Pacheco ,Anke‐Hilse Maitland‐Van Der Zee ,María Pino-Yanes ,Steven Turner ,Esther Herrera‐Luis ,Colin N.a Palmer

doi:10.1371/journal.pone.0257396

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.

Highlights

Asthma is a common chronic inflammation of the airways manifesting as shortness of breath, wheeze and chest tightness that can lead to death, especially in older adults
The Genes-environments and Admixture in Hispanics/Latinos (GALA II) study and the Study of African-Americans, Asthma, Genes, and Environments (SAGE) recruited children from community- and clinic-based centers, with GALA II focused on Hispanics/Latinos and SAGE focused on African Americans [26]
For all studies from the Pharmacogenetics in Childhood Asthma (PiCA) consortium and Tayside randomised clinical trial (RCT), asthmatic individuals under montelukast treatment were selected by a physician and information such as age, sex, body mass index (BMI) and oral corticosteroids (OCS) use, hospitalization and exacerbation were available from a questionnaire filled at patient enrolment

Summary

Introduction

Asthma is a common chronic inflammation of the airways manifesting as shortness of breath, wheeze and chest tightness that can lead to death, especially in older adults. Asthma shares common genetics with allergic diseases [9], none all individuals with allergic asthma respond to steroids [10] This add to the emerging evidence of asthma genetic heterogeneity defining different underlying biological mechanisms, which should help predict the patients’ likely responses to treatment [11]. We focused our analysis on a particular variant in the regulatory region of the leukotriene-A4 hydrolase (EC3.3.2.6) gene (LTA4H), the single nucleotide polymorphism (SNP) rs2660845 This variant has been shown to influence montelukast response through the prevention of exacerbations in a cohort of young adults with asthma from the United States [14] as well as improvement of pulmonary parameters such as peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) in a Japanese cohort [16]. We wished to determine if age of asthma onset status further refined this putative pharmacogenomic association to provide the beginnings of a precision medicine strategy for the treatment of asthma with montelukast

Study design

Results

Discussion