Chang Xiao, MD, PhD, Jocelyn M

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Presentation transcript:

Vanin-1 expression and methylation discriminate pediatric asthma corticosteroid treatment response Chang Xiao, MD, PhD, Jocelyn M. Biagini Myers, PhD, Hong Ji, PhD, Kelly Metz, MD, Lisa J. Martin, PhD, Mark Lindsey, BS, Hua He, MS, Racheal Powers, BS, Ashley Ulm, BS, Brandy Ruff, Mark B. Ericksen, BS, Hari K. Somineni, MS, Jeffrey Simmons, MD, Richard T. Strait, MD, Carolyn M. Kercsmar, MD, Gurjit K. Khurana Hershey, MD, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 4, Pages 923-931.e3 (October 2015) DOI: 10.1016/j.jaci.2015.01.045 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Overview of approach identifying genes with expressions in nasal epithelial cells that discriminate pediatric asthma corticosteroid treatment response. B, Expression of SOD2, HCK, SRGN, and VNN1 was quantified by using qRT-PCR. C, VNN1 expression was quantified in the discovery and replication cohorts. qRT-PCR results are expressed as average fold change at T1 relative to T0, with glyceraldehyde-3-phosphate dehydrogenase as the internal control. Journal of Allergy and Clinical Immunology 2015 136, 923-931.e3DOI: (10.1016/j.jaci.2015.01.045) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, Upper panel, CpG4 percentage methylation at T0 versus T1 in good (P = .07) and poor (P = .16) responders. Lower panel, Percentage of patients with increased (black bars) and decreased (white bars) methylated CpG4 levels at T1 versus T0 in good and poor responders. P = .003. B, Positive correlation between the percentage change in VNN1 CpG4 methylation and fold change in VNN1 mRNA expression. P = .02, Pearson r = 0.58. Journal of Allergy and Clinical Immunology 2015 136, 923-931.e3DOI: (10.1016/j.jaci.2015.01.045) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A-C, Representative AHR (Fig 3, A), total BALF cell counts (Fig 3, B), and percentage differential BALF cells (Fig 3, C) in WT and VNN1−/− mice treated with saline, HDM, or HDM plus dexamethasone (HDM+Dex; n = 6-8 per group). Fig 3, A: ***P < .001, WT-HDM versus WT-HDM+Dex; ***P < .001, VNN1−/−-HDM versus VNN1−/−-HDM+Dex; #P < .05, WT-HDM+Dex versus VNN1−/−-HDM+Dex. Fig 3, B-F: *P < .05, ***P < .001, and ##P < .01. D-F, Percentage reduction in AHR (Fig 3, D, ∗∗P < .01), total BALF cell counts (Fig 3, E), and percentage BALF eosinophils (Fig 3, F) in mice treated with HDM+Dex (n = 20-28 per group). G-L, Data are from 4 independent experiments. Hematoxylin and eosin staining of lung tissues collected from WT (Fig 3, G, I, and K) and VNN1−/− mice (Fig 3, H, J, and L) is shown. Also, mice treated with saline (Fig 3, G and H), HDM (Fig 3, I and J), and HDM plus dexamethasone (Fig 3, K and L) at a magnification of ×200 are shown. Insets show infiltrated eosinophils at a magnification of ×1000. Journal of Allergy and Clinical Immunology 2015 136, 923-931.e3DOI: (10.1016/j.jaci.2015.01.045) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Proposed model. At baseline, the VNN1 gene is modestly expressed, and this level of expression is not altered in patients with stable or acute asthma. During treatment for an AAE, corticosteroid treatment induces DNA methylation at the CpG4 site of the VNN1 gene promoter, enhancing expression of the VNN1 gene. Enhanced VNN1 expression contributes to optimal response to corticosteroid treatment. Journal of Allergy and Clinical Immunology 2015 136, 923-931.e3DOI: (10.1016/j.jaci.2015.01.045) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions