UBC Faculty Research and Publications

Identification of a functional SNP in an asthma gene: IL1RL1 Akhabir, Loubna; Sandford, Andrew Nov 26, 2010

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POSTER PRESENTATION Open AccessIdentification of a functional SNP in an asthmagene: IL1RL1Loubna Akhabir*, Andrew SandfordFrom Allergen NCE Inc.’s Fifth Annual Research Conference: Innovation from Cell to SocietyQuébec City, QC, Canada. 7-9 February 2010BackgroundOur aim is to identify causal variants for the IL1RL1gene previously associated with asthma and related phe-notypes as well as perform functional assays to uncoverthe mechanism underlying its involvement in the diseasepathogenesis. IL1RL1 has been shown to be sufficient toinduce experimental allergic airway inflammation usingtransgenic and knockdown mouse models. Its expressionhas been shown to increase in murine and human asth-matic lungs; the ligand for IL1RL1 is Interleukin-33(IL33). The signaling cascade resulting from the bindingof TSLP and IL33 is crucial in eosinophilic inflammationcharacteristic of asthma. The IL1RL1 gene lies in chro-mosome 2 in the midst of a cytokine gene cluster withIL1R1, IL1RL2, IL18R1 and IL18RAP: all encoding forproteins involved in the immune response characteristicof asthma. The region is in relatively high linkage dise-quilibrium, thus an excellent candidate for narrowingdown the asthma association signal to one or more cau-sal SNPs.MethodsFirstly, a putative causal SNP is identified based on pre-vious association data, or linkage disequilibrium withassociated SNPs, conservation scores and putative bind-ing of regulatory proteins.DNA samples from asthmatics and controls are thengenotyped for the candidate SNP using Taqman tech-nology in order to relate genotypes to potential altera-tion of gene expression.Gene expression assays will be performed to comparelevels of expression between the different genotypes aswell as between the two SNP alleles. These real time-polymerase chain reaction (RT-PCR) experiments willbe conducted for both IL1RL1 isoforms in order to alsoassess their differential expression depending on ourcandidate SNP genotype. If changes in expression areobserved, we will perform electrophoretic mobility shiftassays in order to test if the differential expression isdue to the differential binding of a regulatory proteindepending on the SNP allele. In order to further con-firm that the SNP site is in an important region forgene expression regulation we will perform formalde-hyde-assisted isolation of regulatory elements (FAIRE); amethod which discriminates between DNA sequencesdepending on the presence or lack of nucleosome struc-tures. The absence of nucleosome indicates that theregion is active and accessible to regulatory elementsand thus important for gene regulation.FindingsWe have selected the IL1RL1 SNP rs1420101 based onthe fact that it was the most significant signal in a gen-ome-wide study about eosinophil counts and the sameSNP associated with asthma in ten populations in thesame study. During the optimization phase of our geneexpression assays, we confirmed differential expressionof the IL1RL1 isoforms in RNA samples from blood ofasthmatic children as well as controls. The next step isto relate that differential expression to the SNP geno-type as well as continue with RT-PCR to compareallele-specific expression.Conclusions and relevanceThe overall objective of this research is to enhance ourunderstanding of the pathogenesis of asthma by narrow-ing down genetic association signals to specific causalvariants. Not only will this strengthen the evidence forIL1RL1 being an asthma gene but it will also helpuntangle the association signal from this region. Reach-ing a greater understanding of the molecular* Correspondence: loubna.akhabir@hli.ubc.caUBC James Hogg Research Centre, Providence Heart+Lung Institute,Vancouver, BC, CanadaAkhabir and Sandford Allergy, Asthma & Clinical Immunology 2010, 6(Suppl 3):P1http://www.aacijournal.com/content/6/S3/P1 ALLERGY, ASTHMA & CLINICAL IMMUNOLOGY© 2010 Akhabir and Sandford; licensee BioMed Central Ltd.pathogenesis of asthma will eventually pave the way fornovel therapies targeting the source of inflammationrather than life-long therapies aimed at dampeninginflammation and easing symptoms.Published: 26 November 2010doi:10.1186/1710-1492-6-S3-P1Cite this article as: Akhabir and Sandford: Identification of a functionalSNP in an asthma gene: IL1RL1. Allergy, Asthma & Clinical Immunology2010 6(Suppl 3):P1.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitAkhabir and Sandford Allergy, Asthma & Clinical Immunology 2010, 6(Suppl 3):P1http://www.aacijournal.com/content/6/S3/P1Page 2 of 2


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