International Collaborators Identify New
Genetic Risk Factors for MS
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Medical Update Memo
July 31, 2007
Summary
The International Multiple Sclerosis Genetics
Consortium (IMSGC) has identified two new genetic
variations associated with MS, completing the
largest replicated whole genome scan (scan
of all the genes in the body) for multiple
sclerosis to date. In addition, two independent
collaborating groups published papers in Nature
Genetics confirming one of these gene variations.
The findings point to potential mechanisms
underlying the disease and present possible
new targets for designing better therapies
to stop the immune attack in MS. The IMSGC,
a group of international MS genetic experts
created with funding from the U.S. National
MS Society, report their results in The
New England
Journal of Medicine (published early online
July 29, 2007). The U.S. MS Society and Harvard
united to jointly raise a total of $3.63 million
to fund this genome scan study.
“By pinpointing genes that elevate the
risk of developing MS and other autoimmune
diseases,” stated Dr. John R. Richert,
Executive Vice President, Research & Clinical
Programs at the National MS Society, “these
studies lead us in new directions for both
treating and eventually preventing these diseases.” All
of the data from the gene scan is being made
publicly available to aid future research.
Details
A major effort has been under way for over
a decade to search for the genetic underpinnings
of MS, looking for the inherited set of genes
that make people susceptible to developing
the disease. If successful, it would give scientists
a roadmap to the cause of MS, as well as to
concrete targets for new therapies and possibly
even ways to prevent the disease. But this
painstaking search, involving analysis of the
genome and the banking of thousands of DNA
samples from patients and family members, has
not yet borne fruit beyond several possible “hot
spots” on areas of the 23 pairs of ribbon-like
chromosomes which require further exploration.
The Genome Scan Study: Using a new technological
advance, a DNA chip that enabled the collaborators
to test 500,000 individual genetic locations
(sites within genes) at one time for possible
involvement in MS, they scanned blocks of the
genome all the genes in the human body for
variations that were more commonly inherited
by people with MS compared to those without
the disease. They screened the genome in 931 “trio
families,” which comprised people with
different types of MS and their unaffected
parents.
To double-check their findings, they performed
a second analysis of other sets of families,
individual cases of MS and a control group.
Ultimately, all samples were combined for
a final analysis of more than 12,000 people.
This is the first genome scan in MS in which
the results were replicated, which is a crucial
step in establishing the validity of results.
High-powered analysis yielded two novel genetic
variations showing a highly significant association
with MS. These variations are in the genes
that control the function of messenger proteins,
or cytokines, that regulate immune cells including
T cells, major players in the immune attack
that is launched on the brain and spinal cord
in MS. The variations are in the genes for
interleukin-2 receptor-alpha and interleukin-7
receptor-alpha. Interleukin-2 and Interleukin-7
have been associated with certain T cells (called
regulatory T cells) that have the power to
turn off the immune attack and there is evidence
of dysfunction of these cells in MS. Interleukin-2-alpha
has previously been implicated in other autoimmune
diseases, including type 1 diabetes.
Two Confirming Studies: Two papers published
online July 29 in Nature Genetics also report
on the association of interleukin-7 receptor-alpha
with MS, and how the change in this protein
affects the immune system. One is by Drs. Jonathan
Haines (Vanderbuilt University Medical Center),
Margaret Preicak-Vance (University of Miami
Miller School of Medicine) and an international
group of collaborators and was funded in part
by the National MS Society. This team explored
three possible candidate MS genes that had
been pinpointed by previous studies, but was
only able to confirm that the gene for interleukin-7
receptor alpha was associated with MS. They
also found evidence that the gene variation
may alter the amount of interleukin-7 receptor
alpha that is available, possibly leading to
impaired suppression of autoimmunity.
The second Nature Genetics paper is by Drs.
Frida Lundmark and Jan Hillert (Karolinska
Institute, Stockholm, Sweden) and collaborators
from Sweden, Denmark, Finland, and Norway.
To follow up their previous study identifying
interleukin-7 receptor alpha as a possible
susceptibility gene in MS, the group conducted
a series of studies in people with MS and people
without MS, all of which confirmed the association
of this gene with susceptibility to MS.
Implications: Taken together, the findings
of all three studies point to potential mechanisms
underlying the disease and present possible
new targets for designing better therapies
to stop the immune attack in MS. Already under
testing in people with MS is the monoclonal
antibody “daclizumab” (PDL BioPharma
and Biogen Idec), which targets interleukin-2
receptor-alpha.
Investigators agree that the identification
of these two new genetic risk factors is unlikely
to change current clinical practice, and that
there are likely many more genes that contribute
to disease susceptibility. “This study
also uncovered a number of other genes that
approached statistical significance, some of
which may relate to the risk of developing
MS,” added Dr. Richert. “As these
additional genes are probed further for their
role in MS, not only will we understand a great
deal more about the cause of MS, but a number
of important new therapeutic targets will emerge.”
For many years the MS Society of Canada has
also funded genetic studies which have yielded
among other things, much information about
the familial susceptibility factors.
ASK MS Information System Code: 2.6.k
Adapted from the National MS Website
Disponible en français.
Disclaimer
The Multiple Sclerosis Society of Canada is an independent, voluntary health
agency and does not approve, endorse or recommend any specific product or
therapy, but provides information to assist individuals in making their own
decisions.
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