Non-genetic components associated with the risk of developing MS

Summary

The exact combination of factors that trigger the onset of MS remain unknown. Evidence shows that the onset is related to genetic factors, infections, and environmental factors (such as exposure to sunlight). The term ‘epigenetics’ refers to the regulation of gene activity, which does not involve changes to the DNA sequence itself but rather slight chemical modifications of the DNA. Dr Maltby will examine the role of epigenetics in the onset of MS.

In a preliminary study, the team at the Hunter Medical Research Institute found that one particular type of epigenetic change – called DNA methylation – was different in people with MS and healthy individuals. They found that the majority of these changes occur around an area containing multiple genes known to play a large role in the development of MS, called the major histocompatibility locus. The genes in this area are known also to play a large role in immunity. Treating MS as an autoimmune disorder, Dr Maltby will further study the changes identified in this region and assess other, related epigenetic changes in the region. She will endeavour to determine whether they contribute to MS disease onset. She is also investigating if these epigenetic profiles can be altered by current MS treatments.

A better understanding of the epigenetic profiles of immune cells will provide new insight into the disease mechanisms underlying MS. Additionally, this study will hopefully identify epigenetic changes that could be used for predicting prognosis and/or treatment effect.

Project Outcomes

Dr Maltby has completed a number of research studies during her fellowship. The first study included looking at the methylation patterns of 30 people with relapsing-remitting MS, 24 with secondary progressive MS, and 40 people without MS. Dr Maltby found different methylation patterns between people with relapsing remitting MS and secondary progressive MS, and three specific methylation signals were seen in genes of people with relapsing remitting MS that were not seen in the people who did not have MS. These signals corresponded to three of the genes known to be associated with a person’s risk of developing MS.

Comparing the people with secondary progressive MS to people with relapsing remitting MS showed that the people with secondary progressive MS had much higher levels of methylation overall. Dr Maltby’s group found that in people with secondary progressive MS there were methylation changes that were specific to these patients, and these changes may provide part of the switch from relapsing remitting MS to the secondary progressive phase of disease. Dr Maltby and her team then recruited an additional group of people with secondary progressive MS and repeated the analysis to check if the findings could be repeated. Their findings held true in the second group, reinforcing the importance of this discovery.

Another study was undertaken to test whether receiving MS treatment led to differences in DNA methylation. Dr Maltby examined the levels of methylation before treatment and six months after the start of treatment with dimethyl fumarate. Dr Maltby and her team found that there were a number of methylation changes after treatment, and in particular some changes that would control the gene activity of four specific genes. Further work is needed to determine whether the changes are due to the treatment itself or whether they reflect the stabilisation of the disease in these people. To answer this question, Dr Maltby and her colleagues will now look at methylation in people using two additional disease modifying therapies to see if a similar effect happens.

A better understanding of the epigenetic profiles of immune cells will provide new insight into the disease mechanisms underlying MS and point to new targets for therapy.

As a result of her excellent work during this Fellowship, Dr Maltby has been successful in obtaining further grants for her ongoing research. She aims to determine whether epigenetic changes could be used for predicting prognosis and quickly identifying whether treatments are working. This will potentially help with the rapid optimisation of treatment for individuals.

Publications

Groen K, Lea RA, Maltby VE, Scott RJ, Lechner-Scott JLS. Letter to the editor: blood processing and sample storage have negligible effects on methylation. Clin Epigenetics. 2018 Feb 10:22.
Maltby VE, Lea RA, Sanders KA, White N, Benton MC, Scott RJ, Lechner-Scott J. Differential methylation at MHC in CD4⁺ T cells is associated with multiple sclerosis independently of HLA-DRB1. Clin Epigenetics. 2017 Jul 18;9:71
Sanders KA, Benton MC, Lea RA, Maltby VE, Agland S, Griffin N, Scott RJ, Tajouri L, Lechner-Scott J. Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4⁺ T cells. Clin Epigenetics. 2016 Aug 27;8(1):87.
Groen K, Maltby VE, Sanders KA, Scott RJ, Tajouri L, Lechner-Scott J. Erythrocytes in multiple sclerosis – forgotten contributors to the pathophysiology? Multiple Sclerosis Journal – Experimental, Translational and Clinical. 2016 May 2: 1-9.
Maltby VE, Graves MC, Lea RA, Benton MC, Sanders KA, Tajouri L, Scott RJ, Lechner-Scott J. Genome-wide DNA methylation profiling of CD8+ T cells shows a distinct epigenetic signature to CD4+ T cells in Multiple Sclerosis patients. Clinical Epigenetics. 2015 Nov 5;7:
Vicki E Maltby, Rod A Lea, Karen A Ribbons, Katherine A. Sanders, Daniel Kennedy, Myintzu Min, Rodney J. Scott, and Jeannette Lechner-Scott. DNA methylation changes in CD4⁺ T cells isolated from multiple sclerosis patients on dimethyl fumarate. Under review
Vicki E. Maltby, Rodney A. Lea, Moira C. Graves, Katherine A. Sanders, Miles C. Benton, Lotti Tajouri, Rodney J. Scott and Jeannette Lechner-Scott. A hypermethylated region in the promoter of the lymphotoxin-alpha gene in CD19+ B cells is associated with multiple sclerosis. Under review
Kira Groen, Vicki E Maltby, Rodney A Lea, Katherine A Sanders, J. Lynn Fink, Rodney J Scott, Lotti Tajouri, Jeannette Lechner-Scott. Erythrocyte microRNA sequencing reveals differential expression in relapsing-remitting Multiple Sclerosis. Under review
Vicki E Maltby, Rodney A Lea, Katherine A Sanders, Rebecca Seeto, Kira Groen, Rodney J Scott, Lotti Tajouri, Jeannette Lechner-Scott. Interplay of microRNA biogenesis, miR-29b and DNA methylation in CD4⁺ T cells from secondary progressive multiple sclerosis patients. Manuscript in preparation.