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Mapping QTL affecting a systemic sclerosis-like disorder in a cross between UCD-200 and red jungle fowl chickens
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2012 (English)In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 38, no 2, 352-359 p.Article in journal (Refereed) Published
Abstract [en]

Systemic sclerosis (SSc) or scleroderma is a rare, autoimmune, multi-factorial disease characterized by early microvascular alterations, inflammation, and fibrosis. Chickens from the UCD-200 line develop a hereditary SSc-like disease, showing all the hallmarks of the human disorder, which makes this line a promising model to study genetic factors underlying the disease. A backcross was generated between UCD-200 chickens and its wild ancestor - the red jungle fowl and a genome-scan was performed to identify loci affecting early (21days of age) and late (175days of age) ischemic lesions of the comb. A significant difference in frequency of disease was observed between sexes in the BC population, where the homogametic males were more affected than females, and there was evidence for a protective W chromosome effect. Three suggestive disease predisposing loci were mapped to chromosomes 2, 12 and 14. Three orthologues of genes implicated in human SSc are located in the QTL region on chromosome 2, TGFRB1, EXOC2-IRF4 and COL1A2, as well as CCR8, which is more generally related to immune function. IGFBP3 is also located within the QTL on chromosome 2 and earlier studies have showed increased IGFBP3 serum levels in SSc patients. To our knowledge, this study is the first to reveal a potential genetic association between IGFBP3 and SSc. Another gene with an immunological function, SOCS1, is located in the QTL region on chromosome 14. These results illustrate the usefulness of the UCD-200 chicken as a model of human SSc and motivate further in-depth functional studies of the implicated candidate genes.

Place, publisher, year, edition, pages
2012. Vol. 38, no 2, 352-359 p.
National Category
Genetics Immunology
URN: urn:nbn:se:uu:diva-182840DOI: 10.1016/j.dci.2012.06.006ISI: 000309312700017PubMedID: 22796227OAI: oai:DiVA.org:uu-182840DiVA: diva2:561033

Correction in: Developmental and Comparative Immunology, vol. 38, issue 4, pg 561.

DOI: 10.1016/j.dci.2012.09.003

Available from: 2012-10-16 Created: 2012-10-16 Last updated: 2016-05-25Bibliographically approved
In thesis
1. Genetic Characterization of Chicken Models for Autoimmune Disease
Open this publication in new window or tab >>Genetic Characterization of Chicken Models for Autoimmune Disease
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autoimmune diseases are endemic, but the disease mechanisms are poorly understood. A way to better understand these are to find disease-regulating genes. However, this is difficult as the diseases are complex, with several genes as well as environmental factors influencing the development of disease. A way to facilitate the search for genes responsible for the diseases is to use comparative genomic studies. Animal models are relatively easy to analyze since control of environment and breeding are obtained.

The University of California at Davies – line 200 (UCD-200) chickens have a hereditary disease that is similar to systemic sclerosis. Using a backcross between UCD-200 chickens and red junglefowl (RJF) chickens we identified three loci linked to the disease. The loci contained immune-regulatory genes suggested to be involved in systemic sclerosis in humans, as well as a previously unidentified linkage between systemic sclerosis in UCD-200 chickens and IGFBP3.

The Dark brown (Db) gene enhances red pheomelanin and restricts expression of eumelanin in chickens. The Db phenotype is regulated by an 8 kb deletion upstream of SOX10. Pigmentation studies are potentially useful when trying to identify pathogenic mechanisms and candidate genes in vitiligo

The Obese strain (OS) of chickens spontaneously develops an autoimmune thyroiditis which closely resembles human Hashimoto’s thyroiditis. By using an intercross between OS chickens and RJF chickens, we found several disease phenotypes that can be used in an ongoing linkage analysis with the goal to find candidate genes for autoimmune disease. An important phenotype to record and add to the linkage analysis is autoantibodies against thyroid peroxidase, since this phenotype is a key feature in Hashimoto’s thyroiditis. Previous attempts to measure these titres in OS chickens have failed, hence an assay was developed for this purpose.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 47 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 828
Autoimmune disease, Hashimoto’s thyroiditis, systemic sclerosis, comparative genomics, linkage analysis, OS chickens, spontaneous autoimmune thyroiditis, UCD-200 chickens.
National Category
Genetics Immunology
Research subject
Molecular Medicine
urn:nbn:se:uu:diva-182843 (URN)978-91-554-8506-1 (ISBN)
Public defence
2012-11-29, Enghoffsalen, Akademiska sjukhuset, Ing. 50, Uppsala, 09:15 (Swedish)
Available from: 2012-11-08 Created: 2012-10-16 Last updated: 2013-01-23

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Sahlqvist, Anna-StinaEkwall, OlovAndersson, LeifCarlborg, ÖrjanKämpe, OlleKerje, Susanne
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AutoimmunityDepartment of Cell and Molecular BiologyDepartment of Medical Biochemistry and Microbiology
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