Investigation of the relationship between plasma expression levels and genetic polymorphisms of MIR-146A-5P, MIR-155-5P, MIR-196A2-5P with multiple sclerosis, disability scores and fingolimod therapy

Multiple Sclerosis (MS), the most common cause of non-traumatic neurological disability in young adults, is a chronic inflammatory, autoimmune, neurodegenerative and demyelinating disease of the central nervous system (CNS). Fingolimod is an oral immunosuppressant used in the second-line treatment of relapsing-remitting MS (RRMS), the most common clinical subtype of MS. MicroRNAs (miRNA), which are involved in the regulation of gene expression, are associated with the diagnosis and progression of many diseases and play an important role in biomarker discovery studies. Single nucleotide polymorphisms (SNPs) in the genes of miRNAs influence the expression levels of these miRNAs. In this thesis study, the relation of the circulating expression levels of miR-146a-5p, miR-155-5p and miR-196a-5p, which are associated with the formation of inflammatory and immune responses, and SNPs (rs2910164, rs767649 and rs11614913) in the genes of these miRNAs with the risk of MS disease were investigated. The effects of these SNPs on miRNA plasma expression levels, the role of SNPs in susceptibility to MS in the Turkish population, and the potential of miRNA plasma expression levels as biomarkers for diagnosing MS disease and for monitoring the effects of treatment were evaluated. In Group-1, consisting of 400 RRMS and 400 control participants, genotyping of SNPs MIR146A rs2910164, MIR155 rs767649 and MIR196A2 rs11614913 was performed using real-time polymerase chain reaction. In Group-2, which included 30 naïve (non-treated) RRMS participants, 29 RRMS participants treated with fingolimod and 30 control participants randomly selected from Group-1, plasma relative expressions levels of miR-146a-5p, miR-155-5p and miR-196a-5p were determined by quantitative real-time PCR. Samples were collected at the Ankara Bilkent City Hospital Neurology Polyclinic. In this thesis study, the T allele of the MIR196A2 rs11614913 C/T SNP was found to be associated with the risk of RRMS in the Turkish population, and having the GC or CC genotype of the MIR146A rs2910164 G/C SNP was found to be associated with the risk of rapid MS progression (MSSS>5). The relative expression of miR-155-5p and miR-196a-5p in plasma was statistically significantly lower in RRMS patients treated with fingolimod than in naïve RRMS patients. These results suggest miR-155-5p and miR-196a-5p may be potential therapeutic targets for fingolimod treatment. Within this dissertation study, the association between SNPs MIR146A rs2910164, MIR155 rs767649 and MIR196A2 rs11614913 and the risk of RRMS disease was investigated for the first time in the Turkish population, and it was revealed that the polymorphic T allele of SNP MIR196A2 rs11614913, whose association with MS has not been investigated before, is a risk factor for MS disease in the Turkish population. In addition, the association between the relative expression levels of miR-155-5p and miR-196a-5p in plasma and fingolimod treatment agent was demonstrated. These findings, which reveal potential biomarker candidates in plasma, could enable the development of therapeutics for MS diseases and the production of biosensors to monitor disease progression and response to treatment. This work, which takes a multidisciplinary approach, is described as a study that has made a significant contribution to the field of Biomedical Engineering.