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.

Tengvall, Katarina; Kozyrev, Sergey; Kierczak, Marcin; Bergvall, Kerstin; Farias, Fabiana H G; Ardesjö-Lundgren, Brita; Olsson, Mia; Murén, Eva; Hagman, Ragnvi; Leeb, Tosso; Pielberg, Gerli; Hedhammar, Åke; Andersson, Göran; Lindblad-Toh, Kerstin (2016). 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. BMC genetics, 17(1), p. 97. BioMed Central 10.1186/s12863-016-0404-3

[img]
Preview
Text
art%3A10.1186%2Fs12863-016-0404-3.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (1MB) | Preview

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 ~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 × 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. 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > DermFocus
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Leeb, Tosso

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health

ISSN:

1471-2156

Publisher:

BioMed Central

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

12 Jul 2016 15:45

Last Modified:

12 Jul 2016 15:45

Publisher DOI:

10.1186/s12863-016-0404-3

PubMed ID:

27357287

Uncontrolled Keywords:

Atopic dermatitis; Cell type-specific enhancers; Dog; Eczema; Genetic association; Luciferase reporter assay; PKP2; Plakophilin 2

BORIS DOI:

10.7892/boris.84125

URI:

https://boris.unibe.ch/id/eprint/84125

Actions (login required)

Edit item Edit item
Provide Feedback