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Cornering multiple sclerosis -- still a long way to go

Multiple sclerosis is an autoimmune disease of the central nervous system that causes neurological disability in young adults. Several environmental and genetic factors have been linked to the disease, but the precise mechanisms involved, and whether neurological damage precedes inflammation or vice versa, remain unclear.

In a recent article published in Nature, an international consortium of researchers report the identification of 29 new susceptibility loci, most of which are related to immune system function and, in particular, to T-helper-cell differentiation.

Previous genome-wide association studies (GWAS) that analysed relatively modest numbers of multiple sclerosis patients identified more than 20 risk loci, especially some that encode components of the major histocompatibility complex (MHC). To identify a more complete set of susceptibility loci and obtain new insights into disease mechanisms, an international team of researchers carried out a large GWAS in which they analyzed over 465,000 autosomal single nucleotide polymorphisms (SNPs) from about 9,800 patients and 17,400 controls (that is, people not affected by multiple sclerosis) from 15 countries.

This analysis confirmed 23 loci that had previously been linked to the disease, and revealed another 29 new loci. Most of the risk attributable to the MHC could be accounted by four mutations, one in class-I locus HLA-A and three in class-II locus HLA-DRB1.

A statistical analysis of the functions of the 52 loci (as annotated in the Gene Ontology database) showed that they are enriched for lymphocyte functions. In particular, many genes encoding cell surface receptors (such as CXCR5 and IL7R) with roles in T-helper-cell differentiation showed strong association with multiple sclerosis. In addition, the researchers identified two susceptibility loci with a role in vitamin D synthesis (CYP27B1 and CYP24A1) and others that encode known targets of therapies for multiple sclerosis such as natalizumab (VCAM1) and daclizumab (IL2RA). By contrast, very few genes with known roles in inflammation-independent neurodegeneration were identified.

The overrepresentation of susceptibility genes with roles in T-cell maturation suggests that multiple sclerosis is primarily caused by immune dysfunction, which is followed by neurological damage. However, the 52 variants can explain only ~20% of the heritability of the disease, and therefore a myriad of other susceptibility loci, each adding a tiny percentage to the overall risk of developing multiple sclerosis, remain to be identified.

Original article:
The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2 (2011). Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis Nature, 476 (7359), 214-219 DOI: 10.1038/nature10251

The same story in the news:
- Study identifies 57 genes linked with MS, Multiple Sclerosis Society, UK (10 Aug 2011).
- Multiple sclerosis genes identified in largest-ever study of the disease by Alok Jha, The Guardian (10 Aug 2011).
- Scientists unravel genetic clues to multiple sclerosis by Kate Kelland, Reuters (10 Aug 2011).

During the last 10 months, I have written 18 Research Highlights (short pieces of 300-400 words that summarize recent scientific articles) for Nature Reviews Microbiology. This blog post is based on my first attempt to write a similar piece about a non-microbiological article. However, to make the post more 'blog-friendly', I have embedded some links to definitions of key terms. You can read the definitions by rolling your mouse over the highlighted terms, or you can click on the term to visit a website with more information. Also, I have added a couple of links to news articles that covered the same story.

This post first appeared on Twisted Bacteria, please read the originial post: here

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Cornering multiple sclerosis -- still a long way to go


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