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.