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

Natalia Hernandez-Pacheco; 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 Tantisira; Esteban G Burchard; Anke H Maitland-van der Zee; Carlos Flores; Uroš Potočnik; Maria Pino-Yanes

doi:10.3390/jpm11080733

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

J Pers Med. 2021 Jul 28;11(8):733. doi: 10.3390/jpm11080733.

Authors

Natalia Hernandez-Pacheco^{1

2

3}, Mario Gorenjak⁴, Jiang Li⁵, Katja Repnik^{4

6}, Susanne J Vijverberg^{7

8

9}, Vojko Berce^{4

10}, Andrea Jorgensen¹¹, Leila Karimi¹², Maximilian Schieck^{13

14}, Lesly-Anne Samedy-Bates^{15

16}, Roger Tavendale¹⁷, Jesús Villar^{3

18

19}, Somnath Mukhopadhyay^{17

20}, Munir Pirmohamed²¹, Katia M C Verhamme¹², Michael Kabesch¹³, Daniel B Hawcutt^{22

23}, Steve Turner²⁴, Colin N Palmer¹⁷, Kelan G Tantisira^{5

25}, Esteban G Burchard^{15

16}, Anke H Maitland-van der Zee^{7

8

9}, Carlos Flores^{1

3

26

27}, Uroš Potočnik^{4

6}, Maria Pino-Yanes^{2

3

27}

Affiliations

¹ Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Carretera General del Rosario 145, 38010 Santa Cruz de Tenerife, Spain.
² Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez s/n, Faculty of Science, Apartado 456, 38200 San Cristóbal de La Laguna, Spain.
³ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Avenida de Monforte de Lemos, 5, 28029 Madrid, Spain.
⁴ Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia.
⁵ The Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
⁶ Laboratory for Biochemistry, Molecular Biology, and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000 Maribor, Slovenia.
⁷ Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
⁸ Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Princetonplein 5, 3584 CC Utrecht, The Netherlands.
⁹ Department of Pediatric Respiratory Medicine and Allergy, Emma's Children Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
¹⁰ Department of Pediatrics, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia.
¹¹ Department of Biostatistics, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
¹² Department of Medical Informatics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
¹³ Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
¹⁴ Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
¹⁵ Department of Medicine, University of California, San Francisco, CA 94143, USA.
¹⁶ Department of Bioengineering and Therapeutic Sciences, University of California, 533 Parnassus Ave, San Francisco, CA 94143, USA.
¹⁷ Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital, and Medical School, University of Dundee, Dundee DD1 9SY, UK.
¹⁸ Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Calle Barranco de la Ballena s/n, 35019 Las Palmas de Gran Canaria, Spain.
¹⁹ Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, 30 Bond St, Toronto, ON M5B 1W8, Canada.
²⁰ Academic Department of Paediatrics, Brighton and Sussex Medical School, Royal Alexandra Children's Hospital, 94 N-S Rd, Falmer, Brighton BN2 5BE, UK.
²¹ Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 200 London Rd, Liverpool L3 9TA, UK.
²² Department of Women's and Children's Health, University of Liverpool, Liverpool L69 3BX, UK.
²³ Alder Hey Children's Hospital, E Prescot Rd, Liverpool L14 5AB, UK.
²⁴ Child Health, University of Aberdeen, King's College, Aberdeen AB24 3FX, UK.
²⁵ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
²⁶ Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Polígono Industrial de Granadilla, 38600 Granadilla, Spain.
²⁷ Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, Faculty of Health Sciences, Apartado 456, 38200 San Cristóbal de La Laguna, Spain.

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.

Keywords: childhood asthma; exacerbations; forced expiratory volume in one second; genome-wide association study; inhaled corticosteroids; single nucleotide polymorphism.

Abstract

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