Progressive Multiple Sclerosis Linked to Gene Variation

Research summary: Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

The background

Whilst the cause of multiple sclerosis remains elusive, studies have shown that there are specific variations of genes, known as alleles, which can increase an individual’s susceptibility to developing the disease.  MS is not a classical genetically inherited disorder though, as the presence of these alleles alone is not sufficient to cause disease.  This suggests that it is the interaction between these gene variations in combination with some environmental factor or factors that contribute to the development of MS.

However, there is some suggestion that the effect of these alleles isn’t enough to account for the occasions when MS appears to run in families, known as familial MS.  Being able to identify genes that may play a larger impact could provide insight into the mechanism of disease, as well as help generate more relevant cellular and animal models of disease for research.

The study

This study, conducted by researchers at the University of British Columbia, investigated the exome (all of the genes that are expressed in the body) of two members of a family that has 5 cases of MS over three generations.  The DNA of 4 other individuals of the family that had not been diagnosed with MS was also analysed.  Similarly, a large number of people with MS (n = 2053) and healthy controls (n= 799) were also included.

The findings

Exome sequencing of two people with MS that have a high family incidence of the disease revealed the following:

1. 37 gene variations that were present in less than 1% of the population as found in available databases
2. These variants were then tested across a larger group of 185 controls and 9 further members from the original family.  This allowed for 33 of the 37 gene variants to be excluded, as they were found to either not associate with MS or be present in greater than 1% of the population
3. The final 4 variants were then tested across 2053 people with MS and 799 healthy controls, which showed that a further 3 variants could be excluded due to being found at similar levels in both groups

The final variant involved a substitution in the gene NR1H3, which codes for the Liver X Receptor alpha protein (LXRα).  These proteins are known to be regulators of macrophage function, homeostasis of lipids and inflammation. Whilst the variation was found to associate strongly with disease, it must be noted that it was also found in people that were unaffected, as well as a member of the family under investigation that did not have MS.  This indicates that additional genetic or environmental factors may be required for the onset of MS.

Additionally, the researchers investigated whether the variation in NR1H3 resulted in a specific clinical outcome for the people with MS that had it.  In the family under investigation, it was found that the clinical phenotype tended towards a more progressive form of the disease with quite quick disability progression.  In the larger group analysis, it was found that people with the variation in NR1H3 were 1.35 times more likely to develop primary progressive MS.

The outcomes

This study has identified a new genetic variant that appears to associate with primary progressive MS or a form of relapsing-remitting MS that rapidly transitions to progressive MS.  Although it is strongly associated with disease, the researchers suggest that another initial insult is necessary for MS to develop.

In the article, they hypothesise that an initial damage to myelin in people carrying this variant may rapidly progress due to the gene variation resulting in an innate immune system that is unable to suppress the inflammation and impaired repair mechanisms.  However, this is yet to be conclusively shown.  However, this still provides a novel avenue of therapeutic intervention and being able to manipulate the effected pathway could result in potential treatments for people with progressive MS.

The abstract for this article can be viewed here.

UPDATE

After posting the above summary, Brett had an opportunity to interview A/Prof Carles Vilarino-Guell, who led this investigation.  Here is the recording of their discussion.