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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
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2016 (English)In: BMC Genetics, ISSN 1471-2156, E-ISSN 1471-2156, Vol. 17, 97Article in journal (Refereed) Published
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Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 17, 97
Keyword [en]
PKP2, Atopic dermatitis, Genetic association, Luciferase reporter assay, Cell type-specific enhancers, Dog, Plakophilin 2, Eczema
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-299868DOI: 10.1186/s12863-016-0404-3ISI: 000378844000003PubMedID: 27357287OAI: oai:DiVA.org:uu-299868DiVA: diva2:950246
Funder
Swedish Research Council, 521-2012-2826Swedish Research Council Formas, 221-2009-1689EU, European Research Council, 310203EU, FP7, Seventh Framework Programme, GA-201370
Available from: 2016-07-28 Created: 2016-07-28 Last updated: 2017-11-28Bibliographically approved

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Kozyrev, SergeyKierczak, MarcinMurén, EvaPielberg, GerliLindblad-Toh, Kerstin

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