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Multiple regulatory...
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
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Tengvall, Katarina (författare)
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Kozyrev, Sergey (författare)
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Kierczak, Marcin (författare)
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visa fler...
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Bergvall, Kerstin (författare)
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Farias, Fabiana H. G. (författare)
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Ardesjö-Lundgren, Brita (författare)
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Olsson, Mia (författare)
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Murén, Eva (författare)
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Hagman, Ragnvi (författare)
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Leeb, Tosso (författare)
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Pielberg, Gerli (författare)
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Hedhammar, Åke (författare)
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Andersson, Göran (författare)
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Lindblad-Toh, Kerstin (författare)
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visa färre...
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(utgivare)
- 2016
- 2016
- Engelska.
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Ingår i: BMC Genetics. - 1471-2156. ; 17
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- Natural Sciences (hsv)
- Biological Sciences (hsv)
- Genetics (hsv)
- Naturvetenskap (hsv)
- Biologiska vetenskaper (hsv)
- Genetik (hsv)
Nyckelord
- PKP2
- Atopic dermatitis
- Genetic association
- Luciferase reporter assay
- Cell type-specific enhancers
- Dog
- Plakophilin 2
- Eczema
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Tengvall, Katari ...
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Kozyrev, Sergey
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Kierczak, Marcin
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Bergvall, Kersti ...
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Farias, Fabiana ...
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Ardesjö-Lundgren ...
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visa fler...
-
Olsson, Mia
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Murén, Eva
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Hagman, Ragnvi
-
Leeb, Tosso
-
Pielberg, Gerli
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Hedhammar, Åke
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Andersson, Göran
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Lindblad-Toh, Ke ...
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visa färre...
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