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

Research Article

Göran Andersson¹  Ragnvi Hagman²  Kerstin Bergvall²  Åke Hedhammar²  Mia Olsson³  Tosso Leeb⁴  Eva Murén⁵  Sergey Kozyrev⁵  Marcin Kierczak⁵  Gerli Pielberg⁵  Katarina Tengvall⁵  Fabiana H. G. Farias⁵  Kerstin Lindblad-Toh⁶  Brita Ardesjö-Lundgren⁷ 

[1] Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden;Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden;Department of Medicine, Rheumatology Unit, Karolinska Institute, Stockholm, Sweden;Institute of Genetics, University of Bern, Bern, Switzerland;Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden;Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden;Broad Institute of MIT and Harvard, Cambridge, MA, USA;Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden;Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden;

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

DOI  :  10.1186/s12863-016-0404-3

 received in 2016-02-08, accepted in 2016-06-20,  发布年份 2016

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2016