On genetics and transcriptomics of multiple sclerosis

University dissertation from Stockholm : Karolinska Institutet, Department of Clinical Neuroscience

Abstract: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, where both genetic and environmental factors influence one individual s risk of developing the disease. This thesis is focused on genetic and transcriptomic aspects of MS. Twelve genes have been investigated genetically for their possible independent and interaction mediated effects on MS susceptibility and clinical phenotypes, of which five genes were assessed more thoroughly: HLAA, HLA-DRB1, CD58, HDGFRP3 and RPL5. The MS association with HLA-A was investigated in Study I using a cohort consisting of 1,084 MS patients and 1,347 controls. Logistic regression modelling firmly established an association suggesting a protective effect of the HLA-A'02 allele (OR: 0.63, p-value: 7x10-12). In Study IV CD58, HDGFRP3 and RPL5 were investigated genetically due to previously suggested association in a genome wide association study, and because they had shown differential expression in the CSF of MS patients (Study III). CD58 and RPL5 were confirmed to be associated with MS susceptibility in 1,077 MS patients and 1,217 controls. SNPs in CD58 conferred a multiplicative effect (ORs: 1.4-1.2, p-values: 8x10-5 3x10-2), whereas the effect of RPL5 variants on MS susceptibility was conferred by the heterozygotes (OR: 1.2, p-value: 2x10-2). These genes were suggested to affect MS independently of each other as well as other known risk factors: sex, HLA-DRB1, IL7R, IL2R?, CLEC16A, CD226, SH2B3 and KIF1B. The interplay between these factors was elucidated, and possible epistatic effects were discovered that warrant further investigation. Furthermore, we confirmed the association between HLA-DRB1'15 and lower age at onset, but alleles of neither HLA-A, CD58, HDGFRP3 nor RPL5 were found to affect severity or course of disease in Study II & IV. In Study III gene expression profiling was performed for the first time in CSF cells from MS patients and over 4,000 transcripts were found to be differentially expressed. Simultaneously gene expression was also investigated in peripheral blood lymphocytes (PBL), and patients in an active phase of disease (relapse) were compared to those sampled in remission. These four comparisons revealed that in contrary to cells of the CSF, PBL samples did not show differential expression between MS patients and controls. Intriguingly, when comparing MS patients in relapse to those in remission, PBL samples showed more than 1,000 differentially expressed transcripts whereas in CSF cells no transcripts were differently expressed. Our results imply that MS is accompanied by active and proliferating cells in the CSF, distinguished by the regulation of genes belonging to immune related pathways. The differential expression in blood lymphocytes was characterized by a generally higher expression in relapse but with lower metabolism of several amino acids. The regulation in PBL, but not in CSF cells, implies the importance of peripheral events in driving a disease bout in MS.

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