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Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..ORCID iD: 0000-0002-6163-9540
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article 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.

Place, publisher, year, edition, pages
2016. Vol. 286, no 6, p. 595-608
Keyword [en]
Addison Disease, BACH2 protein, genetic, genetic association studies, genetic predisposition to disease, human, polymorphism
National Category
General Practice
Identifiers
URN: urn:nbn:se:uu:diva-311491DOI: 10.1111/joim.12569ISI: 000388573300007PubMedID: 27807919OAI: oai:DiVA.org:uu-311491DiVA, id: diva2:1060495
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: 2018-01-13Bibliographically approved
In thesis
1. Genetic Studies of Immunological Diseases in Dogs and Humans
Open this publication in new window or tab >>Genetic Studies of Immunological Diseases in Dogs and Humans
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. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1328
Keyword
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:nbn:se:uu:diva-319962 (URN)978-91-554-9901-3 (ISBN)
Public defence
2017-06-05, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2017-05-12 Created: 2017-04-11 Last updated: 2018-01-13

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Bianchi, MatteoLandegren, NilsNordin, JessikaDalin, FridaMathioudaki, ArgyriHultin-Rosenberg, LinaDahlqvist, JohannaKarlsson, AndreasHallgren, AnnaMurén, EvaAhlgren, Kerstin M.Lobell, AnnaTandre, KarolinaRönnblom, LarsMeadows, Jennifer R. S.Lindblad-Toh, KerstinKämpe, OllePielberg, Gerli R.
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