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Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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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.

Place, publisher, year, edition, pages
2015. Vol. 10, no 7, e0133844
Keyword [en]
Genome-wide association studies, Dogs, IgA, immunodeficieny, B-cell
National Category
Medical Genetics Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-259595DOI: 10.1371/ journal.pone.0133844ISI: 000358837700039PubMedID: 26225558OAI: oai:DiVA.org:uu-259595DiVA: diva2:844911
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
In thesis
1. Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency
Open this publication in new window or tab >>Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency
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
GWAS, canine model, genetic association, immunogenetics, atopic dermatitis, IgA deficiency
National Category
Medical Genetics
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-259606 (URN)978-91-554-9304-2 (ISBN)
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

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Publisher's full textPubMedhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133844

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Tengvall, KatarinaKierczak, MarcinAxelsson, ErikLindblad-Toh, Kerstin

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