Association of IL2RA and IL7R genes with MS

Submitted by hollie on Mon, 2007-07-30 13:47.

EXTRA: Because we've received so many queries on this announcement, I've asked Hollie to write up a more detailed description of our response to this news to augment the story submitted by Scott. -art

The hot news in MS today concerns the identification of two genes that are associated with the risk of MS: interleukin 7 receptor alpha chain (IL7R or IL7RA) and interleukin 2 receptor alpha (IL2RA). Many genes have been associated with MS before, and many of these associations have proved shaky upon further investigation, but the evidence behind these two genes is particularly solid owing to the size of the studies and the replication of these results by several teams examining subjects from multiple countries (US, UK, Nordic countries, Belgium).

continued...

Here's an overview of the studies:
International MS Genetics Consortium (IMSGC) (New England Journal of Medicine): This is a “big science,” whole-genome study that analyzed over 300,000 variants in a total of 12,360 MS and control samples (6,717 of these samples were also included in the next study, Gregory et al). Several associations were found in the initial analysis (as you would expect given the large number of genes investigated), but the authors narrowed the field down further and highlighted two genes in particular (IL7RA and IL2RA).

Gregory et al (Nature Genetics): This candidate gene study looked at three genes (MMP19, CCL2, and IL7R) based on past results and wound up finding a significant association for the same IL7R SNP found in the IMSGC study. The authors studied the biological effect of this SNP and concluded that it might reduce the amount of IL7R protein found on the membranes of immune cells and increase the amount of soluble IL7R released from cells.

Lundmark et al (Nature Genetics): This team had previously reported an association for IL7R and conducted a follow-up candidate gene study that included 1,800 Scandinavian MS subjects. They found an association between MS and the same IL7R variant reported in the other studies. They also found higher levels of the IL7R protein and the molecule it binds to, IL7, in the CSF of people with MS compared with controls. (Interestingly, though, no correlation was found between protein levels and IL7R gene variants in these CSF samples.)

The IL7 receptor gene is located on chromosome 5 and the IL2RA gene is on chromosome 10. The proteins these genes encode are involved in the function and regulation of the immune system. For example, IL7R plays a role in T cell differentiation, in the maintenance of T cell populations, and in B cell development. IL2RA (also known as CD25) is expressed on regulatory T cells as well as other cells.

One point that may be missed in some of the news reports describing these studies is that the variants that were associated with MS are very common in the general population. Also, the frequencies in the people with MS were not that much higher than in the controls. For instance, one of the papers (Gregory et al) reports that the IL7R variant associated with MS was found in 76-78% of the MS subjects vs. 72-73% of the control subjects. This is still a statistically significant difference, but not a large one in absolute terms. In contrast, studies of the MS-associated HLA-DR15 haplotype that is also very common in European populations have reported much greater differences between cases and controls (such as 60% vs. 30%, 54% vs. 17%, etc.).

Another interesting point that has been picked up in some reports is that there currently exists a drug that targets one of these proteins. Daclizumab, also known as Zenapax, is a monoclonal antibody against IL2RA. It has shown some efficacy against MS in a couple of small studies, and Biogen will be evaluating it further in an upcoming clinical trial.

My conclusions:

• I applaud the collaboration between groups that enabled the magnitude of these studies -- large scale studies are necessary in MS in order to find risk factors such as these genetic variants that are common in the population at large. This is the basis of the approach the Accelerated Cure Project is taking.
• The genes highlighted in these studies and the HLA genes that have been associated with MS in numerous other studies all perform immune system functions. Perhaps follow-on work resulting from these new associations will help clarify the role of the immune system in MS.
• Because the variants identified in these studies are so common, obviously they cannot represent major risk factors. If they were high-risk factors, then a much greater number of people would have MS. But even though they only increase the risk of MS a little bit, they can serve to indicate focus areas for future research.
• Also, for those (such as us at Accelerated Cure Project) who are looking for the gene-gene and gene-environment interactions that are necessary in the development of MS, these results signify good starting points. For instance, in our repository we could genotype our subjects for IL7R and IL2RA variants and combine these results with data of other types to look for interactions.

http://www.acceleratedcure.org:8080/node/2783