Multiple sclerosis : from genetic variants to biomarkers

Abstract: Multiple sclerosis (MS) is a common chronic autoimmune and neurodegenerative disease of the central nervous system (CNS). MS is a debilitating disease that affects young adults, especially females. Why we develop MS? Is thought to be a consequence of our genes and the environment. In the past four years, the number of MS associated genetic variants have increased up to more than 200, however they explain only about 30% of its heritability. The general aim of the research presented in this thesis is to explore genetic variants associated to MS and to employ our knowledge of the known associations to study their potentiality as biomarkers. In paper I, we aimed to identify genetic variants that distinguish the relapsing relapsing remitting (RR)MS from the primary progressive (PP)MS courses using whole exome sequencing data. We report a number of common and rare variants that are associated to eithercourse. Moreover, we identified enrichment of mutations of other progressive neurological disorders in PPMS patients. In paper II we investigated the possibility of somatic mosaicism within the CNS resulting insub-populations of cells involved in MS pathogenesis. We identified somatic genetic variantsof the copy number variations (CNVs) type in the T cell receptor loci. These CNVs lead us to profile and compare the TCR repertoire in cells in the periphery and in the CNS. A number of potent treatments have been introduced for treating MS patients and they succeeded in providing a better quality of life. In papers III and IV, based on the available information of MS associated genetic variants we studied the effects of two drugs, natalizumab and fingolimod, on the intra-individual profile of proteins within selected pathways with theambition to identify biomarkers for MS treatment. We took a candidate gene approach in paper III and studied the treatment effects on soluble cytokine receptors and observed changes in plasma levels of sIL-7Rα, sIL-2Rα and sgp130. In paper IV we took a multiplex approach utilizing protein arrays and detected a decrease in plasma levels of nine proteins during natalizumab treatment. Furthermore, we validated and replicated the change for the most significant protein, PEBP1. Hopefully the identified genetic variants and observed changes on the molecular level duringtreatment could pave the way to hypotheses generation in order to identify pathways affectedby these variations and provide insight into the immunopathology of MS.