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Genetic Studies of Immunological Diseases in Dogs and Humans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents genetic studies aiming at enlarging our knowledge regarding the genetic factors underlying two immune-mediated diseases, hypothyroidism and autoimmune Addison’s disease (AAD), in dogs and humans, respectively.

Genetic and environmental factors are indicated to contribute to canine hypothyroidism, which can be considered a model for human Hashimoto’s thyroiditis (HT). In Paper I we performed the first genome-wide association (GWA) study of this disease in three high-risk dog breeds (Gordon Setter, Hovawart and Rhodesian Ridgeback). Using an integrated GWA and meta-analysis strategy, we identified a novel hypothyroidism risk haplotype located on chromosome 12 being shared by the three breeds. The identified haplotype, harboring three genes previously not associated with hypothyroidism, is independent of the dog leukocyte antigen region and significantly enriched across the affected dogs. In Paper II we performed a GWA study in another high-risk breed (Giant Schnauzer) and detected an associated locus located on chromosome 11 and conferring protection to hypothyroidism. After whole genome resequencing of a subset of samples with key haplotypes, we fine mapped the region of association that was subsequently screened for the presence of structural variants. We detected a putative copy number variant overlapping with the upstream region of the IFNA7 gene, which is located in a region of high genomic complexity. Remarkably, perturbed activities of type I Interferons have been extensively associated with HT and general autoimmunity.

In Paper III we performed the first large-scale genetic study of human AAD, a rare autoimmune disorder characterized by dysfunction and ultimately destruction of the adrenal cortex. We resequenced 1853 immune-related genes comprising of their coding sequences, untranslated regions, as well as conserved intronic and intergenic regions in extensively characterized AAD patients and control samples, all collected in Sweden. We identified BACH2 gene as a novel risk locus associated with AAD, and we showed its independent association with isolated AAD. In addition, we confirmed the previously established AAD association with the human leukocyte antigen complex.

The results of these studies will hopefully help increasing the understanding of such diseases in dogs and humans, eventually promoting their well-being.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1328
Keyword [en]
complex disease, immunogenetics, autoimmunity, GWAS, NGS, canine model, dog, hypothyroidism, Addison's disease, IFNA, BACH2
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-319962ISBN: 978-91-554-9901-3 (print)OAI: oai:DiVA.org:uu-319962DiVA: diva2:1088214
Public defence
2017-06-05, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-05-12 Created: 2017-04-11 Last updated: 2017-05-16
List of papers
1. A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12
Open this publication in new window or tab >>A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12
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2015 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 10, no 8, e0134720Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-261959 (URN)10.1371/journal.pone.0134720 (DOI)000359353300039 ()26261983 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201370Swedish Research Council, 2009-3376Swedish Research Council, 2012-2826EU, European Research Council, ERC-2012-StG 310203-K9GenesSwedish Research Council Formas, 2009-1689Swedish Research Council Formas, 2010-629
Available from: 2015-09-21 Created: 2015-09-07 Last updated: 2017-04-11Bibliographically approved
2. The Type I Interferon Gene Cluster is Associated with Hypothyroidism in a Swedish Giant Schnauzer Dog Population
Open this publication in new window or tab >>The Type I Interferon Gene Cluster is Associated with Hypothyroidism in a Swedish Giant Schnauzer Dog Population
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(English)Manuscript (preprint) (Other academic)
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-319961 (URN)
Available from: 2017-04-11 Created: 2017-04-11 Last updated: 2017-04-12
3. Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
Open this publication in new window or tab >>Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
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2016 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, 595-608 p.Article in journal (Refereed) Published
Abstract [en]

BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

Keyword
Addison Disease, BACH2 protein, genetic, genetic association studies, genetic predisposition to disease, human, polymorphism
National Category
Family Medicine
Identifiers
urn:nbn:se:uu:diva-311491 (URN)10.1111/joim.12569 (DOI)000388573300007 ()27807919 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseEU, European Research Council, 201167Stockholm County CouncilThe Karolinska Institutet's Research FoundationSwedish Society for Medical Research (SSMF)Swedish Society of MedicineNovo NordiskSwedish Research Council FormasSwedish Rheumatism AssociationÅke Wiberg FoundationAstraZeneca
Available from: 2016-12-28 Created: 2016-12-28 Last updated: 2017-04-11Bibliographically approved

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