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.

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.

Regulatory reform - the review process.

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Effects of regulatory reform on unemployment in the trucking industry. Report to the Honorable Dennis DeConcini, United States Senate.

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Final regulatory analysis of the model year 1982 light truck fuel economy standards.

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The Role of health research in support of EPA's regulatory programs.

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Regulatory analysis proposed premanufacture notification and review procedures : Toxic Substances Control Act, section 5.

"October 1980."

Regulatory impact analysis of emission standards for elemental phosphorus plants /

"EPA 520/1-84-025."

Amending the Financial institutions regulatory and interest rate control act : hearing before the Subcommittee on Financial Institutions Supervision, Regulation and Insurance of the Committee on Banking, Finance and Urban Affairs, House of Representatives, Ninety-sixth Congress, first session, on H.R. 1903 ... February 21, 1979.

"Serial 96-27."

Compliance program reference : inspections of licensed and unlicensed blood banks (compliance program #7342.001) and inspections of source plasma establishments (compliance program #7342.002).

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Energy conservation competes with regulatory objectives for truckers, Interstate Commerce Commission : report to the Congress /

Microfiche: Springfield, Va. : National Technical Information Service. -- (PB 269 746)

Grain inspections : 1960 crops : carload, cargo and trucklot receipts and shipments.

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Regulatory water quality monitoring networks : statistical and economic considerations /

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Maintenance inspections of sixty farm tractors /

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Building regulatory practices and the courts /

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