FROM DISEASE TO THE GENE - Identification of arthritis-regulating loci in rats
(2009) In Lund University Faculty of Medicine Doctoral Dissertation Series 2009:12.- Abstract
- Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic
inflammation of the peripheral joints that eventually leads to cartilage destruction
and bone erosion. The causes of RA remain largely unknown, but considerable
evidence suggests a multifactorial aetiology involving both environmental and genetic
factors. Large efforts have been directed towards the understanding of the molecular
mechanisms underlying RA. Because of the complexity of the disease in humans,
animal models for RA have become attractive tools for gene-identification. Use of
such models not only overcomes genetic complications, but it also permits studies
under stable environmental... (More) - Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic
inflammation of the peripheral joints that eventually leads to cartilage destruction
and bone erosion. The causes of RA remain largely unknown, but considerable
evidence suggests a multifactorial aetiology involving both environmental and genetic
factors. Large efforts have been directed towards the understanding of the molecular
mechanisms underlying RA. Because of the complexity of the disease in humans,
animal models for RA have become attractive tools for gene-identification. Use of
such models not only overcomes genetic complications, but it also permits studies
under stable environmental conditions. However, so far genetic studies using animals
have had only limited success. In fact, researchers have encountered significant
difficulties in the analysis of complex traits.
The first part of this thesis is summarizing two major problems we have faced in the
past years. In the first study we investigated the genetic setup and the response
towards various arthritis models of two DA rat substrains. We detected several genetic
and phenotypic differences, suggesting that one of the substrains had been
genetically contaminated from another rat strain. The second study is based on the
observation that a spontaneous mutation in our DA rat colony results in decreased
arthritis susceptibility in the DA rats. We subsequently isolated the mutation in a
new substrain of DA rats, called DACP, and using genetic linkage analysis we located
the mutation and identified a new quantitative trait locus (QTL) for pristaneinduced
arthritis (PIA) at chromosome 9, Pia27. In the second part of this thesis, we
were utilizing the traditional congenic rat strain strategy in the identification and
characterization of arthritis regulating loci. The third paper investigated the influence
of different genetic backgrounds on the detection of previously reported loci for PIA.
We found that the arthritis-regulating gene Ncf1 as well as the major histocompatibility
complex (MHC) are silent in certain genetic backgrounds, while they
can be detected in other genetic setups. The fourth study describes the positional
cloning of the immunoglobulin lambda light chain (Igl) locus as one locus controlling
rheumatoid factor (RF) production in rats. In addition, evidence suggests that this
genetic region may be associated with Ovalbumin-induced airway inflammation, an
animal model for allergic bronchitis or asthma.
Identification of genes involved in complex disorders such as RA will be extremely
valuable in understanding disease regulating mechanisms as well as improve diagnosis
and identification of specific targets for therapeutic drugs. However, the findings in
this thesis demonstrate that mapping those genes is a complex and challenging
process and involving various problems, such as genetic variability and complex
genetic interactions. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1277671
- author
- Rintisch, Carola LU
- supervisor
-
- Rikard Holmdahl LU
- Thomas Blom LU
- opponent
-
- Saoudi, Abdelhadi, National Institute of Health and Medical Research, Unit 563, University Paul Sabatier, Hospital Purpan, Toulouse, France
- organization
- publishing date
- 2009
- type
- Thesis
- publication status
- published
- subject
- keywords
- Pristane-induced arthritis, Rat strain, Autoimmunity, Rheumatoid arthritis, Quantitative trait locus
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2009:12
- pages
- 40 pages
- publisher
- Department of Experimental Medical Science, Lund Univeristy
- defense location
- BMC Rune Grubb lecture hall
- defense date
- 2009-02-13 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-86059-99-6
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)
- id
- d2b35308-95bd-4183-b984-d74abb065049 (old id 1277671)
- date added to LUP
- 2016-04-01 13:03:35
- date last changed
- 2019-05-21 22:45:56
@phdthesis{d2b35308-95bd-4183-b984-d74abb065049,
abstract = {{Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic<br/><br>
inflammation of the peripheral joints that eventually leads to cartilage destruction<br/><br>
and bone erosion. The causes of RA remain largely unknown, but considerable<br/><br>
evidence suggests a multifactorial aetiology involving both environmental and genetic<br/><br>
factors. Large efforts have been directed towards the understanding of the molecular<br/><br>
mechanisms underlying RA. Because of the complexity of the disease in humans,<br/><br>
animal models for RA have become attractive tools for gene-identification. Use of<br/><br>
such models not only overcomes genetic complications, but it also permits studies<br/><br>
under stable environmental conditions. However, so far genetic studies using animals<br/><br>
have had only limited success. In fact, researchers have encountered significant<br/><br>
difficulties in the analysis of complex traits.<br/><br>
The first part of this thesis is summarizing two major problems we have faced in the<br/><br>
past years. In the first study we investigated the genetic setup and the response<br/><br>
towards various arthritis models of two DA rat substrains. We detected several genetic<br/><br>
and phenotypic differences, suggesting that one of the substrains had been<br/><br>
genetically contaminated from another rat strain. The second study is based on the<br/><br>
observation that a spontaneous mutation in our DA rat colony results in decreased<br/><br>
arthritis susceptibility in the DA rats. We subsequently isolated the mutation in a<br/><br>
new substrain of DA rats, called DACP, and using genetic linkage analysis we located<br/><br>
the mutation and identified a new quantitative trait locus (QTL) for pristaneinduced<br/><br>
arthritis (PIA) at chromosome 9, Pia27. In the second part of this thesis, we<br/><br>
were utilizing the traditional congenic rat strain strategy in the identification and<br/><br>
characterization of arthritis regulating loci. The third paper investigated the influence<br/><br>
of different genetic backgrounds on the detection of previously reported loci for PIA.<br/><br>
We found that the arthritis-regulating gene Ncf1 as well as the major histocompatibility<br/><br>
complex (MHC) are silent in certain genetic backgrounds, while they<br/><br>
can be detected in other genetic setups. The fourth study describes the positional<br/><br>
cloning of the immunoglobulin lambda light chain (Igl) locus as one locus controlling<br/><br>
rheumatoid factor (RF) production in rats. In addition, evidence suggests that this<br/><br>
genetic region may be associated with Ovalbumin-induced airway inflammation, an<br/><br>
animal model for allergic bronchitis or asthma.<br/><br>
Identification of genes involved in complex disorders such as RA will be extremely<br/><br>
valuable in understanding disease regulating mechanisms as well as improve diagnosis<br/><br>
and identification of specific targets for therapeutic drugs. However, the findings in<br/><br>
this thesis demonstrate that mapping those genes is a complex and challenging<br/><br>
process and involving various problems, such as genetic variability and complex<br/><br>
genetic interactions.}},
author = {{Rintisch, Carola}},
isbn = {{978-91-86059-99-6}},
issn = {{1652-8220}},
keywords = {{Pristane-induced arthritis; Rat strain; Autoimmunity; Rheumatoid arthritis; Quantitative trait locus}},
language = {{eng}},
publisher = {{Department of Experimental Medical Science, Lund Univeristy}},
school = {{Lund University}},
series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
title = {{FROM DISEASE TO THE GENE - Identification of arthritis-regulating loci in rats}},
url = {{https://lup.lub.lu.se/search/files/3136945/1278092.pdf}},
volume = {{2009:12}},
year = {{2009}},
}