IL-7R variation linked to MS

In what is the first advance in understanding the genetic underpinnings of multiple sclerosis in 30 years, three research papers published on the same day have found an association between the interleukin-7 receptor alpha (IL-7R) and MS.

While it has been known that there is a strong genetic underpinning for multiple sclerosis, only genes within a region of chromosome 6 have to date been implicated in the disease.

The previously known variants are linked to the human leukocyte system (HLA), part of the major histocompatibility complex (MHC).

The current findings, reported online in the Nature Genetics and the New England Journal of Medicine, demonstrated that IL-7R was associated with an increased susceptibility to the disease.

"Our finding is very important because the genetic factors that are already known to be associated with multiple sclerosis only explain less than half of the total genetic basis for the disease," first author Dr Simon Gregory, a molecular geneticist at Duke University Medical Center's Center for Human Genetics, said.

"We have identified a gene that increases an individual's risk of MS by 30 per cent and that this variant has an effect on the function of the gene."

Their results were confirmed in four independent studies involving individuals of European descent from the US, the UK and Belgium. Jan Hillert and colleagues, studying a large collection of individuals from Denmark, Finland, Norway and Sweden, observed a similar association between variants in IL-7R and multiple sclerosis risk.

In the New England Journal of Medicine paper, David Hafler and colleagues reported results of a genome-wide association scan and follow-up replication study confirming the association between IL-7R and multiple sclerosis risk in a large collection of samples from the US and UK.

Multiple sclerosis is a chronic and debilitating autoimmune disease in which neurons of the central nervous system become demyelinated, resulting in progressive neurodegeneration.

What triggers this autoimmune response is likely a result of a complex interplay between genetic and environmental factors, Gregory said.

IL-7R is present on the surface of some cells and can also be found in the blood serum. The variant thought to be responsible for conferring increased disease risk results in lower levels of the surface-bound form of IL-7R and higher levels of the serum form, report Haines and colleagues.

This change in the relative levels of the two forms of IL-7R may alter the activity of the immune system, rendering individuals who carry the risk variant more susceptible to developing the disease.

It was an Australian team, led by Professor Graeme Stewart and Dr David Booth at the Westmead Millennium Institute, which first proposed a link back in 2003. This Sydney team has been concentrating on IL-7R ever since.

Stewart, a board member of Multiple Sclerosis Australia and director of Westmead Hospital's Institute for Immunology and Allergy Research, also contributed to finding the HLA association when he was a PhD student in the 1970s.

"It took the size (and funding) of the overseas experiments however, and confirmation by results in multiple countries, to make this finding internationally accepted," Stewart said.

"The long time between drinks makes the taste even sweeter but the real joy lies in the potential, albeit perhaps still years away, of better treatments for the many people who live with this dreadful disease and who are long overdue for more effective therapy."

Gregory said that as research builds upon the altered function of IL-7R the mechanisms involved in the development of multiple sclerosis will be unlocked, which may lead to novel treatments for the disease or the identification of targets for new therapies.

The team used genomic convergence, in which they took the results of many studies looking for common elements. From studies involving patients and their families in the US and UK, they analysed more than 7000 DNA samples from patients with confirmed multiple sclerosis and those without the disease.

After narrowing down 28 candidate genes to the IL-7R gene, the researchers then tested their findings on a different set of patient populations to confirm their findings.

The researchers found that the exact same variation in IL-7R increased the risk of multiple sclerosis to a very similar extent in four different populations.