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  • Tengvall, Katarina,1980-Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Uppsala University (author)

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

  • Article/chapterEnglish2016

Publisher, publication year, extent ...

  • 2016-06-29
  • Springer Science and Business Media LLC,2016
  • electronicrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:uu-299868
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-299868URI
  • https://doi.org/10.1186/s12863-016-0404-3DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:133810084URI
  • https://res.slu.se/id/publ/77570URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Kozyrev, SergeyUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)sekoz957 (author)
  • Kierczak, MarcinUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi(Swepub:uu)makie499 (author)
  • Bergvall, KerstinSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences(Swepub:slu)47499 (author)
  • Farias, Fabiana H. G.Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)fabfa647 (author)
  • Ardesjö-Lundgren, BritaSwedish 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(Swepub:slu)96398 (author)
  • Olsson, MiaKarolinska Institutet,Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden (author)
  • Murén, EvaUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)evmur020 (author)
  • Hagman, RagnviSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences(Swepub:slu)50755 (author)
  • Leeb, TossoUniv Bern, Inst Genet, Bern, Switzerland (author)
  • Pielberg, GerliUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)gepie020 (author)
  • Hedhammar, ÅkeSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences(Swepub:slu)49648 (author)
  • Andersson, GöranSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för husdjursgenetik (HGEN),Department of Animal Breeding and Genetics(Swepub:slu)50422 (author)
  • Lindblad-Toh, KerstinUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Broad Inst MIT & Harvard, Cambridge, MA USA(Swepub:uu)kerli865 (author)
  • Uppsala universitetInstitutionen för medicinsk biokemi och mikrobiologi (creator_code:org_t)
  • Sveriges lantbruksuniversitet

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  • In:BMC Genetics: Springer Science and Business Media LLC17:11471-2156

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