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

Sammanfattning: 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.