Sandra Elena-Pérez1, David Hansoe Heredero-Jung1, Asunción García-Sánchez2,3,4, Miguel Estravís2,3,4, Maria J Martin2,4, Jacinto Ramos-González5, Juan Carlos Triviño6, María Isidoro-García1,2,4,7, Catalina Sanz2,4,8, Ignacio Dávila2,3,4,9. 1. Department of Clinical Biochemistry, University Hospital of Salamanca, Salamanca, Spain. 2. Allergic Disease Research Group IIMD-01, Institute for Biomedical Research of Salamanca, Salamanca, Spain. 3. Department of Biomedical Sciences and Diagnostics, University of Salamanca, Salamanca, Spain. 4. Network for Cooperative Research in Health - RETICS ARADyAL, Carlos III Health Institute, Madrid, Spain. 5. Department of Pneumology, University Hospital of Salamanca, Salamanca, Spain. 6. Sistemas Genómicos, Paterna, Spain. 7. Department of Medicine, University of Salamanca, Salamanca, Spain. 8. Department of Microbiology and Genetics, University of Salamanca, Salamanca, Spain. 9. Department of Allergy, University Hospital of Salamanca, Salamanca, Spain.
Abstract
Background: Asthma is a heterogeneous syndrome with a broad clinical spectrum and high drug response variability. The inflammatory response in asthma involves multiple effector cells and mediator molecules. Based on asthma immunopathogenesis, precision medicine can be a promising strategy for identifying biomarkers. Biologic therapies acting on the IL-5/IL-5 receptor axis have been developed. IL-5 promotes proliferation, differentiation and activation of eosinophils by binding to the IL-5 receptor, located on the surface of eosinophils and basophils. This study aimed to investigate the expression of IL5RA in patients with several types of asthma and its expression after treatment with benralizumab, a biologic directed against IL-5 receptor subunit alpha. Methods: Sixty peripheral blood samples, 30 from healthy controls and 30 from asthmatic patients, were selected for a transcriptomic RNAseq study. Differential expression analysis was performed by statistical assessment of fold changes and P-values. A validation study of IL5RA expression was developed using qPCR in 100 controls and 187 asthmatic patients. The effect of benralizumab on IL5RA expression was evaluated in five patients by comparing expression levels between pretreatment and after 3 months of treatment. The IL5RA mRNA levels were normalized to GAPDH and TBP expression values for each sample. Calculations were made by the comparative ΔΔCt method. All procedures followed the MIQE guidelines. Results: IL5RA was one of the most differentially overexpressed coding transcripts in the peripheral blood of asthmatic patients (P = 8.63E-08 and fold change of 2.22). In the qPCR validation study, IL5RA expression levels were significantly higher in asthmatic patients than in controls (P < 0.001). Significant expression differences were present in different asthmatic types. In the biological drug study, patients treated with benralizumab showed a significant decrease in IL5RA expression and blood eosinophil counts. A notable improvement in ACT and lung function was also observed in these patients. Conclusions: These results indicate that IL5RA is overexpressed in patients with different types of asthma. It could help identify which asthmatic patients will respond more efficiently to benralizumab, moving toward a more personalized asthma management. Although further studies are required, IL5RA could play a role as a biomarker and pharmacogenetic factor in asthma.
Background: Asthma is a heterogeneous syndrome with a broad clinical spectrum and high drug response variability. The inflammatory response in asthma involves multiple effector cells and mediator molecules. Based on asthma immunopathogenesis, precision medicine can be a promising strategy for identifying biomarkers. Biologic therapies acting on the IL-5/IL-5 receptor axis have been developed. IL-5 promotes proliferation, differentiation and activation of eosinophils by binding to the IL-5 receptor, located on the surface of eosinophils and basophils. This study aimed to investigate the expression of IL5RA in patients with several types of asthma and its expression after treatment with benralizumab, a biologic directed against IL-5 receptor subunit alpha. Methods: Sixty peripheral blood samples, 30 from healthy controls and 30 from asthmatic patients, were selected for a transcriptomic RNAseq study. Differential expression analysis was performed by statistical assessment of fold changes and P-values. A validation study of IL5RA expression was developed using qPCR in 100 controls and 187 asthmatic patients. The effect of benralizumab on IL5RA expression was evaluated in five patients by comparing expression levels between pretreatment and after 3 months of treatment. The IL5RA mRNA levels were normalized to GAPDH and TBP expression values for each sample. Calculations were made by the comparative ΔΔCt method. All procedures followed the MIQE guidelines. Results:IL5RA was one of the most differentially overexpressed coding transcripts in the peripheral blood of asthmatic patients (P = 8.63E-08 and fold change of 2.22). In the qPCR validation study, IL5RA expression levels were significantly higher in asthmatic patients than in controls (P < 0.001). Significant expression differences were present in different asthmatic types. In the biological drug study, patients treated with benralizumab showed a significant decrease in IL5RA expression and blood eosinophil counts. A notable improvement in ACT and lung function was also observed in these patients. Conclusions: These results indicate that IL5RA is overexpressed in patients with different types of asthma. It could help identify which asthmatic patients will respond more efficiently to benralizumab, moving toward a more personalized asthma management. Although further studies are required, IL5RA could play a role as a biomarker and pharmacogenetic factor in asthma.
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Authors: Jeannette Bigler; Michael Boedigheimer; James P R Schofield; Paul J Skipp; Julie Corfield; Anthony Rowe; Ana R Sousa; Martin Timour; Lori Twehues; Xuguang Hu; Graham Roberts; Andrew A Welcher; Wen Yu; Diane Lefaudeux; Bertrand De Meulder; Charles Auffray; Kian F Chung; Ian M Adcock; Peter J Sterk; Ratko Djukanović Journal: Am J Respir Crit Care Med Date: 2017-05-15 Impact factor: 21.405