Multiple sclerose: van genetisch profiel naar geïndividualiseerde behandeling

Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation, demyelination and axonal loss. Like most autoimmune diseases, MS is a complex disease with susceptibility controlled by the interplay of environmental and genetic factors. The past few years have seen important progress in the understanding of MS. Epidemiological studies have provided strong evidence for three environmental risk factors: Epstein‑Barr virus infection, sunlight exposure and smoking. A genetic component in the risk of multiple sclerosis hadlong been demonstrated by family studies but it was the emergence of high‑throughput genotyping which led to a major breakthrough in the identification of MS susceptibility variants. Currently, a list of five risk factors located in the human leukocyte antigen (HLA) region and 110non‑HLA risk factors show convincing evidence for association with MS susceptibility. An issue that remains unresolved is the remarkably heterogeneity observed between patients in terms of clinical features (age at onset, disease course and disease severity) as well as paraclinical features (degree of autoantibody production and treatment response). It is thought that complex interactions of multiple environmental and genetic factors do not only influence MS susceptibility but may also play an important role in modifying disease course. Reliable biomarkers capturing the different aspects of heterogeneity are necessary to untangle MS into different subtypes. Therefore the overall focus of my PhD project was to discover genetic factors defining patient subgroups characterized by common pathways, similar disease progression and treatment response, which may benefit from an individualized approach. In the first part of my PhD thesis I evaluated whether subgroups of MSpatients exist defined by less common (minor allele frequency (MAF)=1-5%), rare (MAFFamilial Mediterranean fever (FMF) is an autosomal recessiveauto‑inflammatory disorder caused by mutations in the Mediterranean fever (MEFV ) gene. Small scale studies reported a two- to four-fold higher co‑occurrence of FMF and MS compared to what is expected by chance. In order to evaluate if a subgroup of MS patients exists with an auto‑inflammatory tendency, we screened a large Belgian MS study population. Our study demonstrates that rare non‑synonymous MEFV variants do not influence MS susceptibility or severity of disease. However, they define a subgroup of MS patients at risk for severesystemic side‑effects when treated with the first‑line therapy interferon‑béta (IFN-β). Further validation in a larger and more diverse study group is necessary before this biomarker can be brought from identification to clinical application. A recent study observed that carrying one copy of a mutation in the cytochrome P450 family 27 subfamily B polypeptide 1 (CYP27B1 ) gene, implicated by a common MS risk variant, is associated with lower active vitamin D levels andhigher risk to develop MS. To verify the existence of a subgroup of MS patients characterized by vitamin D deficiency, we set out to replicate this finding. The most common mutation R389H does not increase risk of MS in the Belgian or Italian MS population, as was in the mean time confirmed by studies investigating other MS populations. Furthermore, normal biochemical profile was observed in carriers of CYP27B1 mutations and sequencing of 134 patients of multiplex families discovered no otherpathogenic variants. Hence, our data do not warrant the previously suggested screening and vitamin D replacement therapy in CYP27B1 mutation carriers. Genetic variation near the galacotosylceramidase (GALC ) gene is one of the few known MS susceptibility factors thatis not shared with other autoimmune diseases but has a neurological function . Rare mutations and copy number variations in the GALC gene are known to cause the autosomal recessive Krabbe disease, a metabolic disorder affecting the myelin sheath of the central and the peripheralnervous system. A subgroup of individuals with mutations in GALC maypoint to a neurological pathway crucial in MS, as opposed to the immunological pathways implicated by most common risk variants. Our data cannot explain t he effect of the most strongly associated common SNP (rs74796499) on MS susceptibility through linkage disequilibrium with a rare or less common coding variant, neither through lowering GALC enzyme activity or influencing splicing of exon 4. However, an underrepresentation of the most common mutation in European Krabbe disease patients (30kbdeletion) and a duplication located in exon 13 was observed in MS patients compared to healthy unrelated controls. This observation was not significant possibly due to the low frequency of this variant. In the second part of my PhD thesis I investigated whether a genetic component defines subgroups of MS patients in which a more pronounced humoral component is present. The presence of antibody production in the central nervous system (CNS) is the hallmark in the diagnosis of MS. A high inter‑individual variation is observed in MS patients: some have levels that are not distinguishable from healthy controls, whereas for others they are continuously as high as in infectious disorders. Our study investigated the genetic component influencing threemeasures of cerebrospinal fluid (CSF) antibody production (oligocolonalband (OCB) status, OCB count and immunoglobuline G (IgG) index) in MS. Our data together with data from previous studies confirmed that the OCB status and IgG index are in part genetically determined. Themajor determinants of CSF antibody production are the HLA and immunoglobulin heavy chain (IGHC) regions, defining a group of MS patients characterized by a higher degree of humoral antibody production, which may benefit from the use of novel B cell depleting therapies. Examination of the overlaps and differences between autoimmune diseases can inform us about general and disease‑specific pathways. Sinceseveral studies have provided evidence for a genetic component influencing the production of a variety of autoantibodies, we investigated whether overlap in genetic factors influencing autoantibody production existsbetween MS, autoimmune thyroid disease (AITD) and ulcerative colitis. Our study observed that genetic factors influencing autoantibody production differ between autoimmune diseases. However, similar to the situationof heterogeneity in MS, we observed a subgroup of AITD patients characterized by an increased thymic output depending on TSHR genotype. Thisincreased thymic output of the Graves disease associated TSHR risk allele is observed in Graves diseases as well as Hashimoto thyroiditis patients but not in healthy controls, strongly suggesting that it is driven by a disease‑genotype interaction. Althougha great deal of progress has been made in MS susceptibility and extensive research is currently being performed to find reliable biomarkers, a great challenge is ahead to go from bench to bedside. Just as for the discovery of MS susceptibility variants, large collaborations will be necessary to drive biomarker research from identification to validation and clinical application.status: publishe