Positional cloning of a novel gene influencing asthma from Chromosome 2q14

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Abstract

Asthma is a common disease in children and young adults. Four separate reports have linked asthma and related phenotypes to an ill-defined interval between 2q14 and 2q32 (refs. 14), and two mouse genome screens have linked bronchial hyper-responsiveness to the region homologous to 2q14 (refs. 5,6). We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14. We sequenced the surrounding region and constructed a comprehensive, high-density, single-nucleotide polymorphism (SNP) linkage disequilibrium (LD) map. SNP association was limited to the initial exons of a solitary gene of 3.6 kb (DPP10), which extends over 1 Mb of genomic DNA. DPP10 encodes a homolog of dipeptidyl peptidases (DPPs) that cleave terminal dipeptides from cytokines and chemokines, and it presents a potential new target for asthma therapy.

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Figure 1: LD map of the locus associated with asthma and location of initial DPP10 exons.
Figure 2: EMSA of WTC122P.
Figure 3: Exon structure of DPP10.
Figure 4: Cellular location of fusion proteins from transcripts 1 and 2.
Figure 5: Tissue expression of DPP10.
Figure 6: Cytokines and chemokines containing penultimate PxS motifs.

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References

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Acknowledgements

We thank D. Gordon for support; L. Cardon for statistical and other advice; the people of Busselton and the many individuals who helped with their clinical testing; the subjects in other panels of individuals and families for their participation; and R. Hennion, S. Lees, J. Herbert, N. Robinson and J. Faux for their supporting contributions to experiments. Testing of unrelated severe asthmatics was supported by the Asmarley Trust. The study was funded by the Wellcome Trust and the National Asthma Campaign. E.Y.J. is a Cancer Research UK Principal Fellow.

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Correspondence to William O C M Cookson.

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The University of Oxford holds a patent protecting the commercialization of the DPP10 gene and protein. Authors of this paper employed by the University of Oxford may benefit financially from commercialization of the patent.

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