Current Gene‐Mapping Strategies in Experimental Models of Multiple Sclerosis

Abstract

Both family-based linkage analyses and population-based association studies have failed to identify disease-regulatory non-human leucocyte antigen genes of importance in multiple sclerosis (MS). Instead, investigators have employed experimental models, which offer major advantages in genetic studies. We summarize the current main methodologies used and the status of both the human and experimental approaches. Why is it important to find genes regulating MS? There is an immense number of cellular and molecular interactions defined in the immunological field and it is very difficult to unravel those that are critical to an inflammatory disease, such as MS, by classical hypothesisdriven research. Unbiased genetics defines evolutionary conserved gene polymorphisms and pathways regulated by these genes, which are central in the pathogenesis. These, in turn, are of interest as therapeutic targets and pharmacogenetic markers. Genetic epidemiology of multiple sclerosisMultiple sclerosis (MS) is a chronic inflammatory disease, which affects the central nervous system (CNS) and causes neurological deficits. The prevalence of MS in high-risk areas, such as northern and central Europe, Italy, the middle part of Northern America, southeastern Australia and New Zealand, is more than 30 per 100,000. Both genetic and environmental factors contribute to the development of MS. The first evidence for a genetic contribution to MS, the association with certain human leucocyte antigen (HLA) haplotypes, was reported about 30 years ago [1,2]. Observations in twin studies and familial aggregation studies, however, reflect the relevance of non-HLA genes and polygeneity in MS [3,4]. Despite this, it remains unresolved whether specific genes are crucial for the development of MS and if so, how many. The current hypothesis describing the influence of genetics on multifactorial diseases suggests an interaction of multiple genes. There are, however, still no unequivocal demonstrations of discrete genes regulating the susceptibility or the disease course of MS. Therefore, it is unclear how many genes that might be of relevance, the strength of their impact (relative risk or odds ratio) and their potential differential distribution among different ethnic groups and/or families. In contrast to monogenic diseases, gene-environment interactions are also suggested to play a crucial role, as well as stochastic events for passing the level for the induction of disease [5]. Genomewide scans and candidate gene approaches in MSAttempts to identify non-HLA susceptibility genes in MS have been based on genomewide linkage analysis and candidate gene approaches. The first four family-based genomewide analyses in MS were published in 1996 and in 1997: Canada [6], France and the US [7], the UK [8] and Finland [9]. There were no significant linkages detected in any of these studies. Nonetheless, some regions showed maximum logarithm of odds (LOD) score >0.5 and were identified in more than one genomewide scan. The highest LOD scores were obtained for ...

Definition of a 1.06-Mb Region Linked to Neuroinflammation in Humans, Rats and Mice

“…Substantial amounts of data have been generated in linkage and association studies of MS (Kenealy et al 2003) as well as in genetic studies of the animal model, experimental autoimmune encephalomyelitis (EAE) in rats and mice (Olsson et al 2000;Andersson and Karlsson 2004;Becanovic et al 2004). However, apart from the HLA complex (Hillert and Olerup 1993;Weinshenker et al 1998), many decades of MS research have as yet failed to determine an unequivocal gene that governs disease susceptibility.…”

Specific and Strain-Independent Effects of Dexamethasone in the Prevention and Treatment of Experimental Autoimmune Encephalomyelitis in Rodents

“…Better understanding of the different genetic profile and the multiple immunopathogenic pathways that seem to underlie the different clinical forms of MS is therefore a prerequisite for better and more focused therapeutic approaches [10][11][12][13][14].…”

Sex, MHC and complement C4 in autoimmune diseases

“…Although these results appear to be contradictory, the role of IFN-g in MS and EAE is both protective and detrimental depending upon the stage of disease [15]. The status of both human and other animal genetic approaches related to MS have been reviewed recently [16].…”