Exploring MicroRNA as a Biomarker for Multiple Sclerosis (EMBleMS): A Pilot Study
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Multiple Sclerosis, a leading cause of disability in young adults, is typically diagnosed as relapsing remitting at onset, however, most patients will eventually transition to a progressive course. This secondary progressive form is difficult to identify and typically not treated therapeutically due to its altered pathology, except in cases of active secondary progression wherein relapses still occur along with continued worsening of neurologic dysfunction. Identifying a biomarker for this phenotype would improve recognition of the progressive transition and lessen prognostic uncertainty. This pilot study explored the use of microRNAs as biomarkers in patients with relapsing remitting and secondary progressive multiple sclerosis. The study hypotheses were: 1. The expression levels of microRNAs that affect the vitamin D receptor biosynthesis pathway is different in relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, and healthy controls and 2. The expression levels of microRNAs affecting the vitamin D receptor biosynthesis pathway is different in more severe forms of multiple sclerosis, measured by an expanded disability status scale score of 4.5 compared to multiple sclerosis patients with less disability, measured by an expanded disability status scale score of < 4.5. The framework for the study was the central dogma of biology which describes the transcription of genetic code from deoxyribonucleic acid to ribonucleic acid to a protein. The small, 22-nucleotide microRNAs silence genes during translation, affecting protein expression, and has been implicated in the pathogenesis of other illnesses, such as cancer. Vitamin D is related to immune system functioning and low vitamin D has been associated with multiple sclerosis risk and poor prognosis while higher levels of vitamin D may improve multiple sclerosis outcomes by decreasing inflammatory processes. The vitamin D receptor gene may be immune modulating, influencing tumor growth rate, severity of disease, and treatment outcomes in cancers and other diseases. While there is much unknown about the links between vitamin D, the vitamin D receptor gene, and multiple sclerosis, there is evidence to warrant exploration into its potential involvement in the pathology and the contributing effects of microRNAs that affect the vitamin D biosynthesis pathway. This study used a three-group comparison design to explore serum circulating microRNA expression levels in relapsing remitting multiple sclerosis (N = 15), secondary progressive multiple sclerosis (N = 15), and healthy controls (N = 15). A second analysis compared the microRNA expression levels of those with greater progression to those with less disability, measured using the expanded disability status scale. The pilot study tested a custom assay designed to target seven microRNAs thought to affect the vitamin D receptor gene. The 30 participants with multiple sclerosis were in remittance and receiving treatment for multiple sclerosis, as applicable; the 15 healthy controls were free from serious illness that would preclude them from participation in the view of the principal investigator. The multiple sclerosis cohort and healthy controls both consisted of an 80/20% female-male ratio and were over the age of 18 with a mean age of 56.3 years. Results of a Kruskal-Wallis H-test did not support the hypothesis that the expression profile of microRNAs that affect the vitamin D receptor biosynthesis pathway is different in relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, and healthy controls (p > .05). Results of a Mann-Whitney U test observed that the mean relative expression levels of let-7a (p = .038), miR-27b (p = .007), and miR-125b (p = .032) were higher in those with less disability than in individuals with greater disability, supporting the second hypothesis. This study adds to the body of knowledge concerning microRNAs that correlate with multiple sclerosis disability and creates interest in the vitamin D receptor biosynthesis pathway for further exploration as to its involvement in multiple sclerosis disability progression and the inflammatory process. The current study additionally provides support for nurse scientists to become emerging leaders in the field of genetic and genomic research.
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Introduction -- Review of Literature -- Methods -- Results -- Discussion -- Appendix
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Ph.D. (Doctor of Philosophy)