Identification of robo2 as a potential locus associated with inhaled corticosteroid response in childhood asthma

Natalia Hernandez-Pacheco (Lead / Corresponding author), Mario Gorenjak, Jiang Li, Katja Repnik, Susanne J. Vijverberg, Vojko Berce, Andrea Jorgensen, Leila Karimi, Maximilian Schieck, Lesly Anne Samedy-Bates, Roger Tavendale, Jesús Villar, Somnath Mukhopadhyay, Munir Pirmohamed, Katia M.C. Verhamme, Michael Kabesch, Daniel B. Hawcutt, Steve Turner, Colin N. Palmer, Kelan G. TantisiraEsteban G. Burchard, Anke H. Maitland-Van der Zee, Carlos Flores, Uroš Potočnik, Maria Pino-Yanes

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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.

Original languageEnglish
Article number733
Number of pages17
JournalJournal of Personalized Medicine
Volume11
Issue number8
DOIs
Publication statusPublished - 28 Jul 2021

Keywords

  • Childhood asthma
  • Exacerbations
  • Forced expiratory volume in one second
  • Genome-wide association study
  • Inhaled corticosteroids
  • Single nucleotide polymorphism

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