Although most cases of the common neurological disease multiple sclerosis (MS) occur only once within a family, some families have two or more members with MS. We have carried out genetic studies on the DNA of individuals within these families including those unaffected as well as affected. A stretch of DNA shown to be present more often in those affected compared to those unaffected was discovered several decades ago. This is a particular variation of a gene within the major histocompatibility complex (MHC) which has many functions relating to immunity. The particular variation initially detected was HLA-DRB1*15 which is the strongest genetic association to MS.
Prof Ebers has led a study investigating the genetic susceptibility to MS and other possible risk factors for over 30 years. Various members of the Ebers group, past and present, have collected DNA and life-style information from Canadian patients and their families and we now have over 35,000 DNA samples which we have used to answer many questions about the occurrence of MS.
For example, the frequency of MS increases with distance from the equator, suggesting one risk factor may be lack of sunlight or vitamin D, which is only synthesised in the body when sunlight is of sufficient strength. We have recently demonstrated a direct link between Vitamin D and HLA-DRB1*15 where vitamin D binds to a stretch of DNA near to HLA-DRB1*15 altering the amount of protein produced from this gene.
We also noticed that mothers tend to contribute more to disease development than fathers. This is known as the maternal effect and we have been trying to identify why this is the case. We are currently looking at how some DNA is chemically modified, essentially turning the gene or genes on/off where the modification is present and whether or not this may be passed down through generations, possibly predisposing to disease.
In terms of genetics, work undertaken by us has also demonstrated that the picture is more complicated than originally thought. As each person has two copies of all genes, they will have two of HLA-DRB1. This is a highly variable gene and there are many possible different variations or ‘alleles’ which may be present. Recent studies by the Ebers group have shown that there are more alleles than just HLA-DRB1*15 involved in susceptibility and in fact some alleles provide protection against developing MS. Our work also suggests that there can be an inter-play of particular alleles within patients to further increase or decrease risk.
We have also found alleles that make it more likely that if you develop MS it will be of a mild form. We are continuing to study this and other nearby areas of DNA in the hope of understanding all genetic contributions to susceptibility in this area.