|After a Decades-Long Search, Scientists
Identify New Genetic Risk Factors for Multiple Sclerosis
A pair of large-scale genetic studies supported by the National
Institutes of Health has revealed two genes that influence the
risk of getting multiple sclerosis (MS) — data sought since
the discovery of the only other known MS susceptibility gene decades
ago. The findings could shed new light on what causes MS — a
puzzling mix of genes, environment and immunity — and on
potential treatments for at least 350,000 Americans who have the
"These studies describe the first genes conclusively linked to
MS in more than 20 years," said Ursula Utz, Ph.D., a program director
at the National Institute of Neurological Disorders and Stroke
(NINDS), a part of NIH. "This breakthrough was made possible through
persistence, an elegant search strategy, and genomic data and techniques
that were not available until recently."
Both studies involved scanning DNA samples from more than 20,000
MS patients and unaffected individuals in the U.S. and Europe,
and looking for single nucleotide polymorphisms (SNPs), which are
single-letter variations in a gene's DNA code. Published simultaneously
today in the New England Journal of Medicine and Nature Genetics,
the studies demonstrate an association between MS and SNPs in two
genes that encode interleukin receptors, proteins that serve as
antennae on the surface of immune cells.
Both studies were supported by NINDS and the National Multiple
Sclerosis Society. The Nature Genetics study received additional
support from the National Institute of General Medical Sciences
(NIGMS). The NEJM study was also supported by the National Institute
of Allergy and Infectious Diseases (NIAID), the National Center
for Research Resources (NCRR) and the Penates Foundation.
They were conducted by overlapping teams of scientists that used
different gene-hunting strategies. One team, which scanned the
entire human genome for MS risk factors, was co-led by David Hafler,
M.D., Professor of Neurology at Harvard Medical School and Brigham
and Women's Hospital in Boston, Stephen Hauser, M.D., Professor
and Chair of Neurology at the University of California in San Francisco,
and Alastair Compston, FRCP, Ph.D., Head of the Department of Clinical
Neurosciences at the University of Cambridge, U.K. The other team,
which focused their search on a set of genes they considered potential
risk factors for MS, was co-led by Jonathan Haines, Ph.D., Director
of the Center for Human Genetics Research at Vanderbilt University
Medical Center in Nashville, Tenn. and Margaret A. Pericak-Vance,
Ph.D., Director of the Miami Institute for Human Genomics at the
University of Miami. Drs. Hauser, Compston, Haines and Pericak-Vance
participated in both studies.
MS typically causes limb weakness, vision loss and problems with
coordination, and is the most common disabling neurological disorder
of young adults. It's an autoimmune disease, occurring when the
body's immune system mistakenly attacks a protective sheath around
axons — the delicate cables that nerve cells use to connect with
each other. Various immunosuppressant drugs can reduce symptoms
and slow the disease's course, but most MS patients become increasingly
disabled with time.
The trigger for MS is unclear, though there's strong evidence
for an interplay between genetic susceptibility and some type of
environmental factor. Having a relative, especially an identical
twin, with MS increases one's risk of developing the disease. In
the mid-1970s, researchers discovered that human leukocyte antigens
(HLA) account for some of this genetic susceptibility. HLAs are
proteins displayed on all the body's cells to help the immune system
distinguish self from non-self. A variant of the HLA-DRB1 gene,
now widely accepted as the strongest genetic risk factor for MS,
increases the likelihood of getting the disease up to four-fold.
Still, HLA does not fully explain the genetic basis of MS; scientists
have long realized that other genes must play a role that has been
difficult to detect. Some studies have pointed to other HLA genes,
but neither of the two genes reported today belong to that category.
Both genes encode receptors on the surface of T cells — the immune
system's mobile infantry — that enable the cells to respond to
regulatory, secreted proteins called interleukins.
"These are the first non-HLA genes to be unequivocally associated
with MS," said Dr. Pericak-Vance. "They give us a new way of looking
at the biology of the disease, and could be targets for therapeutic
Both studies searched for a link between MS and SNPs that were
previously identified by the HapMap, an NIH-supported project to
catalog genetic differences in human populations.
In the genome-wide association study, the first of its kind in
MS, the researchers used gene chip technology to scan more than
500,000 SNPs. In total, they analyzed more than 13,000 DNA samples,
many of them collected and stored by the Center for Genetic Studies
at the National Institute of Mental Health (NIMH) and the U.K.'s
Wellcome Trust Case Control Consortium. In the candidate gene study,
the researchers scanned DNA samples from four large groups in the
U.S, U.K. and Belgium, totaling more than 10,000 people.
Both studies revealed an association between MS and a single SNP
in the gene interleukin 7 receptor-alpha (IL7R-alpha). The genome-wide
scan also found two SNPs in the gene for interleukin 2 receptor-alpha
(IL2R-alpha) associated with the disease. Both receptors are known
to influence the way that T cells patrol the body for pathogens.
IL2R-alpha has previously been implicated in other autoimmune diseases,
including type 1 diabetes.
Each of the SNPs associated with MS appears to increase the risk
of developing the disease by about 20 to 30 percent. Although that
number might seem small, "it's the size of effect we expect to
see for genes outside of HLA," said Dr. Haines. Multiple genetic
variations, each carrying a small risk of MS, could combine with
one another and with environmental factors to create a large risk,
The researchers who conducted the candidate gene search also think
they know how variation in the IL7R-alpha gene affects the IL7R-alpha
protein. They found evidence that the MS-associated variant causes
a reduction in the amount of the IL7R-alpha protein at the T cell
surface. Less is known about how variation in IL2R-alpha might
contribute to MS, but that protein is already being viewed as useful
therapeutic target. In a 2004 study by NINDS scientists, 10 MS
patients who were unresponsive to currently approved therapies
showed improvement when treated with an antibody that blocks IL2R-alpha,
developed to prevent rejection of organ transplants.
Finally, the genome-wide scan identified nearly a dozen other
genes that could represent risk factors for MS. Some of the associations
were relatively weak and some of the genes' functions are unclear.
"A major effort to understand the full complement of genes involved
in MS will be necessary to completely understand the disease," said
Dr. Hafler, adding that all of the data from the genome scan will
be made publicly available for future investigations.
NINDS (www.ninds.nih.gov) is a component of the National Institutes
of Health (NIH), and is the nationís primary supporter of biomedical
research on the brain and nervous system.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.