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. TantisiraEsteban G. Burchard, Anke H. Maitland-Van der Zee, Carlos Flores, Uroš Potočnik, Maria Pino-Yanes

*Corresponding author for this work

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2 Citations (Scopus)

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
JournalJournal of Personalized Medicine
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2021

Bibliographical note

Funding Information:
This study was supported by the award AC15/00015 funded by the Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Programme framework (MP-Y) and the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020. This study was also funded by the Spanish Ministry of Science, Innovation, and Universities, the State Research Agency, and the European Regional Development Fund from the European Union (MICIU/AEI/FEDER, UE, SAF2017-83417R). N.H-P was supported by a fellowship (FI16/00136) from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Social Funds from the European Union (ESF) ?ESF invests in your future?. MP-Y was funded by the Ram?n y Cajal Program (RYC-2015-17205) by the Spanish Ministry of Science, Innovation and Universities. The PACMAN study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The SLOVENIA study was financially supported by the Slovenian Research Agency (research core funding No. P3-0067) and from SysPharmPedia grant, co-financed by Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106). GALA II was supported by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished in Pharmaceutical Sciences II and the National Institute of Environmental Health Sciences grant R01ES015794. SAGE was funded by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished in Pharmaceutical Sciences II. L.S.B. was supported by National Institute of General Medical Sciences of the National Institutes of Health [5T32GM007546-42]. The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. The PASS study was funded by the NHS Chair of Pharmacogenetics via the UK Department of Health. MP is Emeritus NIHR Senior Investigator. ESTATe was funded by an independent research grant by ZonMw project (113201006). Genotyping of samples from BREATHE-PAGES, GoSHARE, and SCSGES was carried out at CeGen-PRB3-ISCIII; supported by ISCIII and European Regional Development Fund (ERDF) (PT17/0019).

Funding Information:
Funding: This study was supported by the award AC15/00015 funded by the Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Programme framework (MP-Y) and the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020. This study was also funded by the Spanish Ministry of Science, Innovation, and Universities, the State Research Agency, and the European Regional Development Fund from the European Union (MICIU/AEI/FEDER, UE, SAF2017-83417R). N.H-P was supported by a fellowship (FI16/00136) from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future”. MP-Y was funded by the Ramón y Cajal Program (RYC-2015-17205) by the Spanish Ministry of Science, Innovation and Universities. The PACMAN study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The SLOVENIA study was financially supported by the Slovenian Research Agency (research core funding No. P3-0067) and from SysPharmPedia grant, co-financed by Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106). GALA II was supported by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished in Pharmaceutical Sciences II and the National Institute of Environmental Health Sciences grant R01ES015794. SAGE was funded by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrolment supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished in Pharmaceutical Sciences II. L.S.B. was supported by National Institute of General Medical Sciences of the National Institutes of Health [5T32GM007546-42]. The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. The PASS study was funded by the NHS Chair of Pharmacogenetics via the UK Department of Health. MP is Emeritus NIHR Senior Investigator. ESTATe was funded by an independent research grant by ZonMw project (113201006). Genotyping of samples from BREATHE-PAGES, GoSHARE, and SCSGES was carried out at CeGen-PRB3-ISCIII; supported by ISCIII and European Regional Development Fund (ERDF) (PT17/0019).

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