Identification of ROBO2 as a Potential Locus Associated with Inhaled Corticosteroid Response in Childhood Asthma.

Natalia Hernandez‐Pacheco ,Somnath Mukhopadhyay,Kelan G Tantisira,Andrea Jorgensen,Jiang Li,Munir Pirmohamed,Esteban G Burchard,Uroš Potočnik,Jesús Villar,Maximilian Schieck,Leila Karimi,Katja Repnik,Carlos Flores,Roger Tavendale,Vojko Berce,Michael Kabesch,Mario Gorenjak,Lesly‐Anne Samedy‐Bates ,Susanne Vijverberg ,Katia Verhamme ,Anke‐Hilse Maitland‐Van Der Zee ,Steven Turner ,Daniel B Hawcutt ,Colin N.a Palmer ,María Pino-Yanes

doi:10.3390/jpm11080733

Abstract

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10−6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29–14.93, p = 4.61 × 10−7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10−5), but not in admixed individuals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans.

Highlights

Asthma is the most common chronic disease in childhood and causes a high burden on the quality of life of the patients and their families
A total of 7.5 million common single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 1% with an imputation quality (Rsq) ≥ 0.3 were tested for association with the binary outcome related to the change in FEV1 after Inhaled corticosteroids (ICS) treatment in asthma patients from the SLOVENIA study
Med. 2021, 11, x FOR PEER RErVs1IE1W66980 located in the ROBO2 gene was found to be suggestively (p-value ≤ 5 × 150o−f 61)7 associated with ICS responsiveness in asthma patients (odds ratio (OR) for G allele: 7.01, 95% confidence interval (CI): 3.29–14.93, p = 4.61 × 10−7) (Figures 1 and 2)

Summary

Introduction

Asthma is the most common chronic disease in childhood and causes a high burden on the quality of life of the patients and their families. Asthma has an impact in economic terms on the healthcare system, school, and/or work absenteeism [1,2]. This is a complex respiratory disorder characterized by inflammation and reversible obstruction of airways [3], and with diverse manifestations of symptoms, such as wheeze, breathlessness, chest tightness, and cough [1]. Interindividual differences in ICS response have been described, and differences among different populations and ethnic groups [4,8] These differences have been evidenced to be the result of the interaction of several factors, including comorbidities, environmental exposures, and the clinical characteristics of the disease, among others [9]. The type of asthma (e.g., atopic or non-atopic) could partly

Objectives

Methods

Results

Conclusion