- The rate of progression, severity and long-term outcomes of MS vary significantly between people.
- Factors that affect MS severity and outcomes are poorly understood and may differ from the risk factors for developing MS. Clinicians are currently unable to predict a person’s future disease severity due to a lack of prognostic biomarkers.
- MS Australia-supported researcher Dr Vilija Jokubaitis and her team have investigated the link between genetic and epigenetic changes, and MS severity.
We know that MS onset is a result of a combination of genetic and environmental risk factors, which are likely to differ for each individual.
What is also different for each individual is the rate of progression, severity and long-term outcomes. The factors that affect these remain poorly understood.
Clinicians are currently unable to predict a person’s future disease severity due to a lack of prognostic biomarkers (biological markers or signs). As such, selecting the most appropriate management for the individual remains a clinical challenge.
There are over 230 genetic changes linked to the risk of MS onset, but less is known about the role genetic changes play in disease severity and outcomes.
Some preliminary evidence suggests that genetic changes may influence disease severity, but they do not completely explain it; there are most likely environmental factors at play too.
MS Australia-supported researcher Dr Vilija Jokubaitis, and her team have tried to answer these questions by investigating the genetic and environmental contribution towards MS severity in two separate studies.
Study 1: Genetic changes and disease severity
Using the largest international MS registry, MSBase, a large genetic study and machine learning, Dr Jokubaitis and her team looked at the genetic contribution to MS severity in 1,813 people living with relapsing remitting MS. The study was published in the prestigious journal, Brain.
While the researchers did not find any genetic changes that greatly affected MS severity, they did discover multiple genetic changes that each had a small effect on disease severity.
Further analysis identified two regions of the genome, one in males and the other in females, that potentially cause a difference in disease severity.
The researchers found that many of the genes that contained the identified genetic changes made proteins in the brain and spinal cord, particularly in the cerebellum. These proteins had various functions, including in the biology of myelin-producing cells (oligodendrocytes) and signalling pathways.
From these analyses, the researchers identified six genetic changes with strong evidence for influencing clinical outcomes.
Using a machine learning approach and incorporating genetic changes, together with clinical and demographic data available at disease onset, the researchers were able to predict disease severity with a high level of confidence.
Study 2: Genetics and Epigenetics
One factor that may influence disease severity that has not been investigated previously is epigenetics.
Epigenetics are a set of instructions, or chemical tags added to the DNA sequence, that help control whether particular genes are switched on or off in any given cell.
A visual example of this is the epigenetic tags that control the production of pigments only in certain skin cells to make the zebra’s stripes and the Dalmatian’s spots. These same switches exist in humans too, and can control much more subtle and complex cell functions, such as how immune cells work.
A common type of epigenetic modification is called DNA methylation, the attachment of small chemical groups called methyl groups to the DNA.
Epigenetic mechanisms, such as DNA methylation, are impacted by environmental factors. Therefore, this is a plausible mechanism by which genetic and environmental factors interact to drive disease susceptibility and severity.
To investigate this, Dr Jokubaitis and her team compared DNA methylation patterns between 119 females with mild relapsing remitting MS and 116 females with severe relapsing remitting MS. Published in Clinical Epigenetics, the researchers also tested DNA methylation as a predictive biomarker of disease severity.
The researchers found many differences in DNA methylation between mild and severe disease, with small, but most likely cumulative impacts on MS severity. These differences were largely in genes involved in nerve cell pathways.
To understand the potential of DNA methylation as a predictive biomarker of severity, Dr Jokubaitis and her team compared the accuracy of several models to classify disease severity.
One of the models used clinical data available at diagnosis, including age at onset and first symptoms, while the other models focused on DNA methylation.
The researchers found that the model that used DNA methylation data classified disease severity more accurately than clinical data.
What does this mean?
Together, the two studies show that numerous genetic and epigenetics changes have a small but cumulative effect on disease severity.
These genetic and epigenetic changes may help clinicians predict a person’s future disease severity more accurately than clinical data alone at diagnosis.
While further research is required, this work could pave the way towards improved prognosis and may potentially transform clinical practice.