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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, 1980- (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Uppsala University
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- Kozyrev, Sergey (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Kierczak, Marcin (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Bergvall, Kerstin (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences
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- Farias, Fabiana H. G. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Ardesjö-Lundgren, Brita (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden,Institutionen för husdjursgenetik (HGEN),Department of Animal Breeding and Genetics
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- Olsson, Mia (author)
- Karolinska Institutet,Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden
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- Murén, Eva (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Hagman, Ragnvi (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences
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- Leeb, Tosso (author)
- Univ Bern, Inst Genet, Bern, Switzerland
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- Pielberg, Gerli (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Hedhammar, Åke (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences
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- Andersson, Göran (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för husdjursgenetik (HGEN),Department of Animal Breeding and Genetics
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- Lindblad-Toh, Kerstin (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Broad Inst MIT & Harvard, Cambridge, MA USA
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(creator_code:org_t)
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- 2016-06-29
- 2016
- English.
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In: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 17:1
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Abstract
Subject headings
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- BackgroundCanine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~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.ResultsAdditional 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 × 10−7) and a rare ~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 ~48 kb risk haplotype) that spanned ~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 × 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 (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region.ConclusionsOur 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Genetik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Genetics (hsv//eng)
- LANTBRUKSVETENSKAPER -- Bioteknologi med applikationer på växter och djur -- Genetik och förädling inom lantbruksvetenskap (hsv//swe)
- AGRICULTURAL SCIENCES -- Agricultural Biotechnology -- Genetics and Breeding in Agricultural Sciences (hsv//eng)
Keyword
- PKP2
- Atopic dermatitis
- Genetic association
- Luciferase reporter assay
- Cell type-specific enhancers
- Dog
- Plakophilin 2
- Eczema
Publication and Content Type
- ref (subject category)
- art (subject category)
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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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show more...
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Olsson, Mia
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Murén, Eva
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Hagman, Ragnvi
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Leeb, Tosso
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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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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Genetics
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- AGRICULTURAL SCIENCES
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AGRICULTURAL SCI ...
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and Agricultural Bio ...
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and Genetics and Bre ...
- Articles in the publication
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BMC Genetics
- By the university
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Uppsala University
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Karolinska Institutet
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Swedish University of Agricultural Sciences