Studies of risk loci in multiple sclerosis

Abstract

Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, is one of the most common causes of neurological disability among young adults. While the etiology is unknown, an increasing number of environmental and genetic risk factors is being identified. The major contribution to the genetic risk in MS is by alleles of HLA genes, with the HLA-DRB1*15:01 allele being the strongest risk factor. At present also more than 100 non-HLA loci have been identified. The main objective of the research presented in this thesis was to study genetic variants and their contribution to MS risk.

In Paper I we investigated whether single nucleotide polymorhisms (SNPs) in the region including the IL21 gene, associated with other inflammatory diseases, also contribute to an increased risk for MS. Our results confirmed that this locus does most probably not have a strong effect, if any, on MS risk.

In Paper II we studied protein levels of the CXCL13 chemokine as measured in the cerebrospinal fluid in relation to a number of MS-associated genetic variants. We found that the risk genotypes of HLA-DRB1*15:01 as well as SNPs in the regions of the IRF5, OLIG3/TNFAIP3 and RGS1 genes were associated with increased levels of CXCL13 which has also been suggested as a biomarker for a more severe disease course of relapsing-remitting MS.

In Paper III we performed an analysis of gene-gene interactions between the currently established risk loci in MS and found three pairs of interacting variants with significant interaction effects that departed from additivity of the separate effects of the single variants. We found interactions between HLA-A*02:01 and HLA-DRB1*15:01, the risk allele of rs6677309 and HLA-DRB1*15:01, as well as the risk allele of rs7196953 and HLA-DRB1*03:01. The findings suggest that these pairs of risk factors are involved in the same sufficient causes for MS.

In Paper IV we studied cis-regulation of gene expression by MS associated loci and found several expression quantitative loci in peripheral blood mononuclear cells. We replicated some of them in lymphoblastic cell lines, and observed that one of the eQTLs was also active in CD19+, and another in CD4+ cells. Replications and functional experiments are needed in order to take the results presented in this thesis further in the search for biological pathways involved in MS disease mechanisms.