| 1. |
- Ardesjö-Lundgren, Brita, et al.
(author)
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Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs
- 2017
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In: Veterinary dermatology (Print). - : Wiley. - 0959-4493 .- 1365-3164. ; 28:4, s. 377-e88
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Journal article (peer-reviewed)abstract
- BackgroundCanine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome‐wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin‐2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities.ObjectivesThe main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD‐affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location.Animals/MethodsSkin biopsies were collected from nine CAD‐affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology.ResultsWe observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding‐partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed.ConclusionPlakophilin‐2 protein in dog skin is expressed in both epithelial and immune cells; based on its subcellular location its functional role is implicated in both nuclear and structural processes.
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| 2. |
- Bianchi, Matteo, et al.
(author)
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A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Journal article (peer-reviewed)abstract
- Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds-the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared similar to 167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.
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| 3. |
- Fall, Tove, et al.
(author)
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Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma
- 2015
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In: JAMA pediatrics. - Stockholm : American Medical Association. - 2168-6203 .- 2168-6211. ; 169:11
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Journal article (peer-reviewed)abstract
- IMPORTANCE: The association between early exposure to animals and childhood asthma is not clear, and previous studies have yielded contradictory results.OBJECTIVE: To determine whether exposure to dogs and farm animals confers a risk of asthma.DESIGN, SETTING AND PARTICIPANTS: In a nationwide cohort study, the association between early exposure to dogs and farm animals and the risk of asthma was evaluated and included all children born in Sweden from January 1, 2001, to December 31, 2010 (N = 1 011 051), using registry data on dog and farm registration, asthma medication, diagnosis, and confounders for parents and their children. The association was assessed as the odds ratio (OR) for a current diagnosis of asthma at age 6 years for school-aged children and as the hazard ratio (HR) for incident asthma at ages 1 to 5 years for preschool-aged children. Data were analyzed from January 1, 2007, to September 30, 2012.EXPOSURES: Living with a dog or farm animal.MAIN OUTCOMES AND MEASURES: Childhood asthma diagnosis and medication used.RESULTS: Of the 1 011 051 children born during the study period, 376 638 preschool-aged (53 460 [14.2%] exposed to dogs and 1729 [0.5%] exposed to farm animals) and 276 298 school-aged children (22 629 [8.2%] exposed to dogs and 958 [0.3%] exposed to farm animals) were included in the analyses. Of these, 18 799 children (5.0%) in the preschool-aged children's cohort experienced an asthmatic event before baseline, and 28 511 cases of asthma and 906 071 years at risk were recorded during follow-up (incidence rate, 3.1 cases per 1000 years at risk). In the school-aged children's cohort, 11 585 children (4.2%) experienced an asthmatic event during the seventh year of life. Dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95% CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95% CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95% CI, 1.00-1.07). Results were comparable when analyzing only first-born children. Farm animal exposure was associated with a reduced risk of asthma in both school-aged children and preschool-aged children (OR, 0.48; 95% CI, 0.31-0.76, and HR, 0.69; 95% CI, 0.56-0.84), respectively.CONCLUSIONS AND RELEVANCE: In this study, the data support the hypothesis that exposure to dogs and farm animals during the first year of life reduces the risk of asthma in children at age 6 years. This information might be helpful in decision making for families and physicians on the appropriateness and timing of early animal exposure.
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| 4. |
- Hanson, Jeanette, et al.
(author)
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Naturally Occurring Adrenocortical Insufficiency – An Epidemiological Study Based on a Swedish-Insured Dog Population of 525,028 Dogs
- 2016
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In: Journal of Veterinary Internal Medicine. - : Wiley. - 0891-6640 .- 1939-1676. ; 30, s. 76-84
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Journal article (peer-reviewed)abstract
- Background: Naturally occurring adrenocortical insufficiency (NOAI) in dogs is considered an uncommon disease with good prognosis with hormonal replacement treatment. However, there are no epidemiological studies with estimates for the general dog population. Objectives: To investigate the epidemiological characteristics of NOAI in a large population of insured dogs. Animals: Data were derived from 525,028 client-owned dogs insured by a Swedish insurance company representing 2,364,652 dog-years at risk (DYAR) during the period between 1995–2006. Methods: Retrospective cohort study. Incidence rates, prevalences, and relative risks for dogs with NOAI (AI with no previous claim for hypercortisolism), were calculated for the whole dog population, and for subgroups divided by breed and sex. Mortality rates were calculated and compared in dogs with NOAI and the remaining dogs overall. Results: In total 534 dogs were identified with NOAI. The overall incidence was 2.3 cases per 10,000 DYAR. The relative risk of disease was significantly higher in the Portuguese Water Dog, Standard Poodle, Bearded Collie, Cairn Terrier, and Cocker Spaniel compared with other breeds combined. Female dogs overall were at higher risk of developing AI than male dogs (RR 1.85; 95% CI, 1.55–2.22; P < .001). The relative risk of death was 1.9 times higher in dogs with NOAI than in dogs overall. Conclusion and Clinical Importance: The data supports the existence of breed-specific differences in incidence rates of NOAI in dogs.
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| 6. |
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| 7. |
- Olsson, M., et al.
(author)
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Absolute quantification reveals the stable transmission of a high copy number variant linked to autoinflammatory disease
- 2016
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In: BMC Genomics. - : BioMed Central (BMC). - 1471-2164. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: Dissecting the role copy number variants (CNVs) play in disease pathogenesis is directly reliant on accurate methods for quantification. The Shar-Pei dog breed is predisposed to a complex autoinflammatory disease with numerous clinical manifestations. One such sign, recurrent fever, was previously shown to be significantly associated with a novel, but unstable CNV (CNV_16.1). Droplet digital PCR (ddPCR) offers a new mechanism for CNV detection via absolute quantification with the promise of added precision and reliability. The aim of this study was to evaluate ddPCR in relation to quantitative PCR (qPCR) and to assess the suitability of the favoured method as a genetic test for Shar-Pei Autoinflammatory Disease (SPAID). Results: One hundred and ninety-six individuals were assayed using both PCR methods at two CNV positions (CNV_14.3 and CNV_16.1). The digital method revealed a striking result. The CNVs did not follow a continuum of alleles as previously reported, rather the alleles were stable and pedigree analysis showed they adhered to Mendelian segregation. Subsequent analysis of ddPCR case/control data confirmed that both CNVs remained significantly associated with the subphenotype of fever, but also to the encompassing SPAID complex (p < 0.001). In addition, harbouring CNV_16.1 allele five (CNV_16.1 vertical bar 5) resulted in a four-fold increase in the odds for SPAID (p < 0.001). The inclusion of a genetic marker for CNV_16.1 in a genome-wide association test revealed that this variant explained 9.7 % of genetic variance and 25.8 % of the additive genetic heritability of this autoinflammatory disease. Conclusions: This data shows the utility of the ddPCR method to resolve cryptic copy number inheritance patterns and so open avenues of genetic testing. In its current form, the ddPCR test presented here could be used in canine breeding to reduce the number of homozygote CNV_16.1 broken vertical bar 5 individuals and thereby to reduce the prevalence of disease in this breed.
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| 8. |
- Olsson, Mia, et al.
(author)
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Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Journal article (peer-reviewed)abstract
- Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.
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| 9. |
- Tengvall, Katarina, 1980-
(author)
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Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency
- 2015
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Doctoral thesis (other academic/artistic)abstract
- This thesis presents genetic studies of atopic dermatitis (AD) and IgA deficiency in dogs.AD is a chronic inflammatory and pruritic skin disorder caused by allergic reactions against environmental allergens. Both genetic and environmental factors are involved in the development of Canine AD (CAD) and human AD. In Paper I, we performed genome-wide association studies (GWAS) and identified a locus on chromosome 27 significantly associated with CAD in German shepherd dogs (GSDs). The locus contains several genes and fine-mapping indicated strongest association close to the candidate gene PKP2. In Paper II, we performed additional fine-mapping and identified four highly associated SNPs located in regions with transcriptional regulatory potential in epithelial and immune cells. The risk alleles were associated with increased transcriptional activity and the effect on expression was cell-type dependent. These data indicate that multiple cell-type specific enhancers regulate the expression of PKP2, and/or the neighboring genes YARS2, DNM1L and FGD4, and predispose GSDs to CAD.IgA deficiency is the most common primary immune deficiency disorder in both humans and dogs, characterized by a higher risk of recurrent mucosal tract infections, allergic and other immune-mediated diseases. In Paper III, we performed the widest screening (to date) of serum IgA levels in dog breeds (Ndogs=1267, Nbreeds=22) and defined eight breeds as predisposed to low IgA levels. In Paper IV, we performed GWAS in four of the breeds defined as prone to low IgA levels. We used a novel percentile groups-approach to establish breed-specific cut-offs to perform analyses in a close to continuous manner. In total, 35 genomic loci were suggestively associated (p<0.0005) to IgA levels, and three genomic regions (including the genes KIRREL3 and SERPINA9) were genome-wide significantly associated with IgA levels in GSDs. A ~20kb long haplotype on chromosome 28, significantly associated to IgA levels in Shar-Pei dogs, was positioned within the first intron of the gene SLIT1 overlapping with a possible dog domestication sweep.This thesis suggests novel candidate genes involved in two immune-mediated disorders in the dog. Hopefully, these results will become an important resource for the genetic research of the corresponding human diseases.
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| 10. |
- Tengvall, Katarina, 1980-, et al.
(author)
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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
- 2016
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In: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 17:1
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Journal article (peer-reviewed)abstract
- 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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| 11. |
- Truvé, Katarina, et al.
(author)
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Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus
- 2016
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In: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 12:5
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Journal article (peer-reviewed)abstract
- Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10(-8)). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.
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| 12. |
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| 14. |
- Webster, Matthew T., et al.
(author)
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Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds
- 2015
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Journal article (peer-reviewed)abstract
- Background: The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants. Results: We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves. Conclusions: We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.
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