MS genetic risk further dissected

“The following post is very complex and some of you may find it difficult to get your head around at this stage. Don’t worry we will prepare additional posts to explain genetic studies and what they mean for you and your family.”
Control Consortium. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 10;476(7359):214-9. doi: 10.1038/nature10251.

Studies have shown that genetic factors are primarily responsible for the substantially increased frequency of MS in the relatives of affected individuals. 

Multiplex MS families (more than one affected family member) have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. 
“The MHC is a cluster of genes that the immune system uses to sample the environment within the body to see if there are any infections or tumours to be rejected. It uses this information to remember previous encounters so that in the future it can respond more quickly. From an evolutionary perspective it is a very important set of genes. By far the majority of genetic susceptibility to MS, and many other autoimmune diseases resides in this area.”
Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple genetic variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to MS remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. 
In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, these investigators have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. 
“These genetic loci are common natural variants in our genome and only increase the risk of MS by a small amount. Some of these loci affect how the genes they are in or close to function, which makes them very interesting.”
Within the MHC they have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. 
“This tells us that the risk attributable to the MHC is not simple and involves interactions between these the genes in this area of the genome.”
Immunologically relevant genes are significantly over-represented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
“This confirms the inflammatory hypothesis about MS.”

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