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  • Tengvall, Katarina (author)

Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs

  • E-article/E-chapterEnglish2016

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  • 2016

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  • LIBRIS-ID:21991708
  • http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-299868uri
  • urn:nbn:se:uu:diva-299868urn
  • 10.1186/s12863-016-0404-3doi

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  • Language:English

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  • Published
  • Vetenskapsrådet [521-2012-2826]
  • Forskningsrådet Formas [221-2009-1689]
  • EU, Europeiska forskningsrådet [310203]
  • EU, FP7, Sjunde ramprogrammet [GA-201370]
  • gratis
  • Background: Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a similar to 1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. Results: Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27: 19,086,778 (p = 1.4 x 10(-7)) and a rare similar to 48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the similar to 48 kb risk haplotype) that spanned similar to 280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 x 10(-5)), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27: 19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (p(difference) = 0.003), and also mapped close (similar to 3 kb) to an ENCODE skin-specific enhancer region. Conclusions: Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.

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  • Kozyrev, Sergey (author)
  • Kierczak, Marcin (author)
  • Bergvall, Kerstin (author)
  • Farias, Fabiana H. G. (author)
  • Ardesjö-Lundgren, Brita (author)
  • Olsson, Mia (author)
  • Murén, Eva (author)
  • Hagman, Ragnvi (author)
  • Leeb, Tosso (author)
  • Pielberg, Gerli (author)
  • Hedhammar, Åke (author)
  • Andersson, Göran (author)
  • Lindblad-Toh, Kerstin268427 (author)
  • Uppsala universitetMedicinska och farmaceutiska vetenskapsområdet (publisher)

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  • In:VärdpublikationBMC Genetics171471-2156

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