Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
Multiple sclerosis (MS) is a complex genetic disorder. It is clear that, apart from genes in the HLA region, other susceptibility genes must be involved. Genome searches aiming to identify new genes involved in MS have not yielded consistent results. However, most have been based on affected sib pair studies. The power of these studies is low to identify genes involved in a heterogeneous disorder such as MS. At present, there is increasing interest in extended families with multiple relatives affected to localise genes involved in MS. We have identified 38 patients from a genetically isolated population in the Netherlands. Similar to the findings in a study in an isolated population of Italian origin, MS was found to cluster with type 1 diabetes. After extensive genealogic research, we have linked at present 25 patients to two families. The pedigrees of the patients show multiple loops suggesting a recessive form of disease. In addition, we have identified 80 other multiplex MS families and are making progress in further expanding this material (15-20% of the total MS population belongs to a multiplex family), aiming at 150 families. In the first part of this study we will: 1. localise the gene involved in the disease (genome screen using 420 markers followed by homozygosity mapping) starting with the 25 patients with MS from the families identified, 2. examine the genealogy back to the year ± 1700 of all patients with MS in the region in order to identify new patients linked to these or other pedigrees, 3. investigate clustering in families of MS with other (autoimmune) diseases, such as thyroid disease (which is commonly associated with MS) and type 1 diabetes, 4. try to find other patients linked to these or other pedigrees. This study aims at resulting in a large genome screening program in all pedigrees identified. In the second part of this study we aim to study genetic determinants of the disease course in these well-characterised multiplex MS families. Evidence is now accumulating that not only the cause, but also the course of the disease is associated with genetic factors. Some patients have a benign disease course, whereas others undergo rapid secondary progression leading to substantial disability. It is still impossible to predict the disease course. Better insight into determinants of progression will be of obvious value in patient management, but will also provide insight into the pathogenesis of the disease. Lesion pathology seems dependent on the intensity of the inflammatory reaction on one hand and on the other hand on the vulnerability of axons and their capacity to repair. We hypothesise to find important prognostic genetic determinants in the balance between polymorphisms of pro-inflammatory immune response genes (e.g. IL-1, IFN-gamma, TNF-alpha) and of genes for neurotrophic factors that protect axons and neurons against inflammatory damage, e.g. CNTF, BDNF, NT3 and IGF. Recent studies have provided evidence that myelin reactive T lymphocytes not only cause the demyelinating lesions, but also that they are an important source of protective neurotrophic factors within the same lesions. This suggests that the outcome of inflammation is determined by the capacity of T lymphocytes to secrete neurotrophic factors. Therefore, in our patients and controls we will study in parallel whether, after in vitro T-cell stimulation, the ratio between production of proinflammatory cytokines and neurotrophins distinguishes MS patients from controls and whether higher ratios are associated with a worse disease course. Next to the multiplex families, we will test this in our current cohorts of sporadic MS patients that are followed from the moment shortly after diagnosis. Of course, also the gene(s) identified in the first part of the study will be implemented in studies on the course of the disease. Main collaborating departments will be Genetic Epidemiology and Clinical Genetics (prof. C.M. van Duijn and Prof. B.A. Oostra), Immunology (Dr. J. Laman/prof. R. Benner). Outside Erasmus MC, we collaborate with Prof. R. van Lier (AMC) and Prof. T. Olsson, Karolinska University Stockholm, Sweden.