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Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0003-0424-3571
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 88 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1128
Keyword [en]
GWAS, canine model, genetic association, immunogenetics, atopic dermatitis, IgA deficiency
National Category
Medical Genetics
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:uu:diva-259606ISBN: 978-91-554-9304-2 (print)OAI: oai:DiVA.org:uu-259606DiVA: diva2:846337
Public defence
2015-10-06, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2015-09-11 Created: 2015-08-10 Last updated: 2015-10-01
List of papers
1. Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
Open this publication in new window or tab >>Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
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2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 5, e1003475- p.Article in journal (Refereed) Published
Abstract [en]

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-205345 (URN)10.1371/journal.pgen.1003475 (DOI)000320030000005 ()
Note

Correction in: PLoS Genetics, vol. 11(12):e1005740. doi:10.1371/journal.pgen.1005740

Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2017-12-06Bibliographically approved
2. A risk haplotype within the PKP2 locus shows association to Canine Atopic Dermatitis and contains cell-type specific enhancers
Open this publication in new window or tab >>A risk haplotype within the PKP2 locus shows association to Canine Atopic Dermatitis and contains cell-type specific enhancers
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(English)Manuscript (preprint) (Other academic)
Keyword
Atopic dermatitis, PKP2, Dogs, SNP, genetic fine-mapping
National Category
Medical Genetics
Research subject
Molecular Genetics; Clinical Genetics
Identifiers
urn:nbn:se:uu:diva-259604 (URN)
Funder
Swedish Research Council, 521-2012-2826Swedish Research Council Formas, 221-2009-1689EU, European Research Council, 310203
Available from: 2015-08-10 Created: 2015-08-10 Last updated: 2015-10-01
3. The dog as a genetic model for immunoglobulin A (IgA) deficiency: Identification of several breeds with low serum IgA concentrations
Open this publication in new window or tab >>The dog as a genetic model for immunoglobulin A (IgA) deficiency: Identification of several breeds with low serum IgA concentrations
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2014 (English)In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 60, no 3-4, 255-259 p.Article in journal (Refereed) Published
Abstract [en]

Immunoglobulin A (IgA) serves as the basis of the secretory immune system by protecting the lining of mucosal sites from pathogens. In both humans and dogs, IgA deficiency (IgAD) is associated with recurrent infections of mucosal sites and immune-mediated diseases. Low concentrations of serum IgA have previously been reported to occur in a number of dog breeds but no generally accepted cut-off value has been established for canine IgAD. The current study represents the largest screening to date of IgA in dogs in terms of both number of dogs (n = 1267) and number of breeds studied (n = 22). Serum IgA concentrations were quantified by using capture ELISA and were found to vary widely between breeds. We also found IgA to be positively correlated with age (p < 0.0001). Apart from the two breeds previously reported as predisposed to low IgA (Shar-Pei and German shepherd), we identified six additional breeds in which > 10% of all tested dogs had very low (<0.07 g/l) IgA concentrations (Hovawart, Norwegian elkhound, Nova Scotia duck tolling retriever, Bullterrier, Golden retriever and Labrador retriever). In addition, we discovered low IgA concentrations to be significantly associated with canine atopic dermatitis (CAD, p < 0.0001) and pancreatic acinar atrophy (PAA, p = 0.04) in German shepherds.

Keyword
Immunoglobulin A (IgA) deficiency, Immunodeficiency, Dog, German shepherd
National Category
Immunology in the medical area Veterinary Science
Identifiers
urn:nbn:se:uu:diva-230943 (URN)10.1016/j.vetimm.2014.05.010 (DOI)000340221400014 ()
Available from: 2014-09-03 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
4. Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
Open this publication in new window or tab >>Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, e0133844Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
Genome-wide association studies, Dogs, IgA, immunodeficieny, B-cell
National Category
Medical Genetics Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-259595 (URN)10.1371/ journal.pone.0133844 (DOI)000358837700039 ()26225558 (PubMedID)
Funder
Swedish Research Council, 521-2012-2826, 521-2011-3515Swedish Research Council Formas, 221-2009-1689EU, European Research Council, 310203EU, FP7, Seventh Framework Programme, GA-201370
Available from: 2015-08-10 Created: 2015-08-10 Last updated: 2017-12-04Bibliographically approved

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