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FROM DISEASE TO THE GENE - Identification of arthritis-regulating loci in rats

Rintisch, Carola LU (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:
author
supervisor
opponent
  • Saoudi, Abdelhadi, National Institute of Health and Medical Research, Unit 563, University Paul Sabatier, Hospital Purpan, Toulouse, France
organization
publishing date
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
ISSN
1652-8220
ISBN
978-91-86059-99-6
language
English
LU publication?
yes
id
d2b35308-95bd-4183-b984-d74abb065049 (old id 1277671)
date added to LUP
2009-01-14 18:54:02
date last changed
2016-09-19 08:44:45
@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},
  keyword      = {Pristane-induced arthritis,Rat strain,Autoimmunity,Rheumatoid arthritis,Quantitative trait locus},
  language     = {eng},
  pages        = {40},
  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},
  volume       = {2009:12},
  year         = {2009},
}