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| MS in focus Issue
8
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2006
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Stephen Sawcer, University of Cambridge Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge, UK and Mark Daly, Massachusetts General Hospital, Boston, and The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA |
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The observation that genetic factors influence susceptibility to MS has rightly prompted tremendous efforts to identify the responsible genes, as recognition of these genes will almost certainly implicate the mechanisms responsible for the disease. It is logical to expect that this knowledge will have profound and beneficial effects, eventually allowing us to curtail, cure or even prevent MS.
To date the most important discovery arising from these efforts has been the identification of the association between MS and the “Human Leukocyte Antigens” (HLA). These antigens are proteins which are found on the surface of cells and are important in the process which allows the immune system to distinguish healthy cells from those needing to be removed because, for the tissue does not match, the recipient’s immune system will spot the different set of antigens and reject the organ as foreign and destroy it.
It turns out that certain of these antigens are more common in people with MS than they are in the general population. The strongest association is seen with allele 15 of the HLA-DRB1 gene, a very common allele carried by 1 in 4 people in the UK (25 percent of the population). Thus in the UK, which has a population of approximately 60 million, some 15 million people carry this HLA allele. However, amongst the 60,000 people in the UK who have MS, roughly 60 percent carry the 15 allele. This illustrates some important characteristics of the sort of genetic effects likely to be relevant in MS. First, the vast majority of people who carry the risk allele will not develop the disease – 15 million people carry the 15 allele of HLA-DRB1 but only about 0.3 percent of them develop the disease. In other words, although carrying the 15 allele increases an individual’s chance of developing the disease, the effect is small and more than 99 percent of 15 allele carriers will not develop MS. Second, the allele is not required to develop disease, as some 40 percent of people with MS do not carry this particular risk allele.
Although the association between MS and HLA was first recognised more than 30 years ago, the complexity of this region of the genome is so great that scientists are still trying to discover how it is that inheriting particular HLA alleles manages to influence the risk of developing MS. What is clear is that the HLA genes determine only a small part of the genetic susceptibility to MS. Scientists have long wanted to search the rest of the genome for other similar effects.
Unfortunately the human genome is so large and so variable that there are literally millions of possible genetic factors that could be relevant. Moreover, since the effects exerted by relevant genes are individually modest, each potentially relevant factor needs to be studied in hundreds, perhaps thousands, of people with MS in order to be conclusively identified.
Testing hundreds of thousands, if not millions, of factors in many hundreds, if not thousands, of people has, until now, been a technical impossibility. Previously, scientists searching for the genetic factors influencing susceptibility to MS have only been able to consider a handful of factors from a few carefully selected genes. Sadly these efforts have not produced any consistent findings beyond HLA, but they have taught us much about the methods and problems to be overcome in identifying the genetic causes of MS.
It is now clear that the genetic analysis of MS stands poised to reap the benefits of several decades of academic effort, much of which has been supported by people with MS and MS societies. The requirements for well-powered systematic searches of DNA variation in the human genome are finally in place: large and carefully evaluated groups of people with MS have been engaged in genetic research projects; the Human Genome Project and subsequent projects have provided detailed knowledge about millions of DNA sequence variants in the human genome that might play a role in disease; and a cost effective technology for assessing these DNA variants is just becoming available. Prospects for success are so bright that profitmaking organisations are now entering the field.
There is building enthusiasm that identifying the genes determining susceptibility to MS is within reach. As genes emerge from these studies it will be essential to confirm their relevance by studying more people with MS. Thus, support for continued enrolment of participants should not be forgotten.
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