In one of the largest human genetic studies ever undertaken, scientists have identified the major common genetic variants that contribute to the cause of the devastating neurological disease, multiple sclerosis (MS).
More than 250 researchers participated in the study, spanning 15 countries. Professor Graeme Stewart, Clinical Immunologist the Westmead Millenium Institute, who led the Australian and New Zealand research, explains its significance:
What does this new research add to our existing knowledge of the causes of MS?
We’ve known for a long time that MS results from environmental factors interacting with genetic factors. This study has broken the back of identifying and understanding those genetic factors.
What do the genetic factors tell us?
The study has confirmed 57 MS genes. Each is valuable in its own right and provides a window into the understanding of the cause of the disease.
But when you put 57 pieces onto a jigsaw puzzle, a picture emerges. And the picture that has emerged very clearly is that most of these genes exert their influence through the immune system.
So the study really has proved, beyond doubt, that MS is primarily an auto-immunologic disease.
And, more importantly, it points to the orchestra leaders of the immune system – T cells – as the key to understanding the cause of the disease.
With 57 new insights, how much of the MS puzzle is now complete?
Most of it is complete but certainly not all of it.
These are all common genetic variants. In other words, the disease-associated genetic variant is found in at least 10% of the normal population.
What the study couldn’t identify was the rare genetic variants. But the International MS Genetics Consortium is already attempting to sequence these rare genes.
But much of what’s already been found will drive MS research over the next five to ten years, regardless of what other genes may be discovered.
How much of a role do environmental risk factors play in the development of MS?
There’s quite clearly an environmental component to MS. With identical twins, for instance, if one has MS, the other has MS only a third of the time, despite sharing every single gene. Clearly, the environment is playing a role.
So what do we know about the environment?
We know there’s a very strong correlation between UV exposure, particularly in childhood, and the prevalence of MS.
If you were born and grew up in Tasmania, you have nearly seven times the risk of developing MS as somebody who grew up in Northern Queensland, despite having a similar genetic makeup.
That’s been shown, absolutely conclusively, to correlate with UV light exposure. And the most likely pathway to explain it is the fact that UV light is essential to the production of vitamin D.
Secondly, cigarette smoking is associated with the risk of MS.
Thirdly, infection with the glandular fever virus increases your risk of developing MS.
One of the benefits of finding most of the MS genes is that they can also direct you to potential environmental factors – and this is the most difficult process of all.
The fact that two of these 57 genes are involved in the metabolism of vitamin D adds a lot of weight to the growing hypothesis – based on the UV light exposure data – that vitamin D is an important risk factor in MS.
And UV light is a possible therapeutic agent, either in preventing the disease, or treating very early disease.
How is MS currently treated?
MS is an autoimmune disease, where the immune system attacks the brain rather than just getting on with the task of clearing infections and protecting us from infections and other diseases.
The treatments, at least for the early active phase of MS, have been directed towards blunting the immune response and they’re becoming increasingly effective.
The difficultly is, when you block the immune response, you leave the patient open to the risk of infection and other side effects.
So we need drugs that are not only more effective but are also safer; that more specifically target the autoimmune attack, while leaving the normal immune function in place.
What advances do you expect we’ll see over the next five to ten years?
It’s very hard to predict when these discoveries will turn into new treatments.
Finding a likely candidate drug then leads to a prolonged period of clinical trials. So this won’t be turned around in one or two years – it’s more a five- to ten-year cycle, if not longer.
The process is made particularly lengthy because MS is a slowly evolving disease, so a clinical trial needs to be done over a prolonged period of time to ensure it’s efficacious and safe.
But this gene discovery is a big step forward. I’ve been working on the quest for MS genes for 35 years. We found one in the 1970s, the second in 2007 and now we have 57.
When you find so many genes for MS, you have the ability to look at which of those genes are susceptibility factors for other autoimmune diseases and in this case, it turns out they are.
So research on these MS genes will yield understanding for a raft of other diseases.