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Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling  Manuel A.R. Ferreira,

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Presentation on theme: "Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling  Manuel A.R. Ferreira,"— Presentation transcript:

1 Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling  Manuel A.R. Ferreira, PhD, Rick Jansen, PhD, Gonneke Willemsen, PhD, Brenda Penninx, PhD, Lisa M. Bain, BSc, Cristina T. Vicente, BSc, Joana A. Revez, BSc, Melanie C. Matheson, PhD, Jennie Hui, PhD, Joyce Y. Tung, PhD, Svetlana Baltic, PhD, Peter Le Souëf, FRACP, Grant W. Montgomery, PhD, Nicholas G. Martin, PhD, Colin F. Robertson, FRACP, Alan James, FRACP, Philip J. Thompson, FRACP, Dorret I. Boomsma, PhD, John L. Hopper, PhD, David A. Hinds, PhD, Rhiannon B. Werder, B Biomed Sc, Simon Phipps, PhD  Journal of Allergy and Clinical Immunology  Volume 139, Issue 4, Pages (April 2017) DOI: /j.jaci Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Outline of analytic procedure.
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Summary of association results obtained for 17,190 genes by applying the proposed gene-based test of association to a published asthma GWAS.14 The red horizontal line shows the P value threshold corresponding to an empirical FDR of 5% (P = 1.9 × 10−4). Forty-eight genes exceeded this threshold, including (1) 31 genes located in established risk loci for allergic disease (denoted by +; gene name shown in black font), (2) 6 genes located in new risk loci but with a gene-based association that was driven by trans-eQTLs located in the MHC or near ORMDL3 (denoted by Δ), and (3) 11 genes with a gene-based association that was not driven by eQTLs located in established allergy risk loci (denoted by ○), including 4 (green font) for which the association replicated in an independent GWAS.15 The y axis represents the −log10 value of the simulation-derived gene-based P value, which accounts for the residual LD between eQTLs of a given gene. The P value was based on up to 1 million simulations, and therefore it could not exceed a P value of 10−6 (dashed gray line). Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Expression levels of P2ry13 and P2ry14 in lungs of C57BL/6 mice sensitized and then challenged with a saline solution or an HDM extract. A, Overall gene expression in lung. Expression levels were normalized to Hprt and are expressed as fold change over the saline challenge group. Results show means ± SDs in each group. *Wilcoxon rank sum test: P < .005 when comparing HDM and saline groups. B, D, and E, Expression of P2ry13 and P2ry14 based on flow cytometric analysis in lung epithelial cells or eosinophils and neutrophils collected in BALF after saline or HDM challenge. C, Expression of P2ry13 and P2ry14 in lung sections of mice challenged with saline or HDM. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 In vivo exposure to P2ry13 and P2ry14 receptor agonists in naive C57BL/6 mice. Mice were challenged with either vehicle, one of 3 allergens (HDM, cockroach allergen, or Alternaria species), or one of 3 nucleotides (ATP, UPD-glucose, ADP) and killed 2 and 72 hours after challenge. A, IL-33 expression in BALF collected 2 hours after challenge. B and C, Total numbers of eosinophils (Fig 4, B) and lymphocytes (Fig 4, C) recruited to the BALF at 72 hours after challenge based on flow cytometric analysis. Alt, Alternaria species; CRE, cockroach; Veh, vehicle. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E1 Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E2 Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E3 Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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