Multiple Sclerosis Research Review
Multiple sclerosis (MS) is a chronic disease
that affects the fatty substance called myelin that surrounds
the nerves in the brain and the spinal cord (central nervous
system). Myelin insulates the nerves and enables them to
conduct impulses between the brain and other parts of the
body.
In MS, myelin is lost in multiple areas, leaving
damaged scar tissue (sclerosis). Sometimes the nerve fiber
itself is damaged or broken. When myelin or the nerve fiber
is destroyed or damaged, the nerve's ability to conduct electrical
impulses to and from the brain is disrupted; therefore, nerve
signals have difficulty reaching their destinations.
MS is believed to be an autoimmune disease,
where the body's own defense mechanism attacks the myelin.
Unfortunately, the exact cause of MS is still unknown.
Although MS is not considered an inherited
disorder in the classic sense, there is strong evidence
to support the role of genetic factors in MS. Familial aggregation
has been noted since before the turn of the 20th century and
increased risk to first, second, and third-degree relatives
of individuals with MS have been well documented. This clustering
of MS within families suggests genetic influences on MS susceptibility.
Twin studies and adoption studies also support a strong genetic
component to MS.
Since MS in most families does not follow simple inheritance
patterns (e.g., autosomal
dominant, autosomal
recessive, X-linked),
it is likely that MS susceptibility is largely determined
by multiple and potentially interacting genes, each with a
relatively small contribution to overall risk. Environmental
factors, such as smoking and exposure to viral infections,
are also believed to be involved. MS is an example of a disorder
with a complex
mode of inheritance.
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Significant MS Clues Already Discovered
The Multiple Sclerosis Genetic Group (MSGG) is a collaborative effort between the Center for Human Genetics at Duke University Medical Center, Vanderbilt University Medical Center, the University of California at San Francisco and UC Berkeley. In 1996, the MSGG completed one of the first genomic screens aimed at identifying the location of MS susceptibility regions.
The genomic screen used 471 individuals from 80 families and the strongest evidence for an MS susceptibility gene was found in a region on chromosome 6 known as the Major Histocompatibility Complex (MHC). The MHC group of genes acts as the "master switch" for our body's immune system. This finding supports the hypothesis that MS is an autoimmune disease. Since the publication of this genomic screen, many other research groups have conducted similar studies, which confirmed the important role of the MHC in contributing to MS and also suggested other chromosomal regions likely to harbor MS susceptibility genes.
The MSGG second-generation screen of a much larger number of MS families was completed and published in 2004, and the research group is currently following up the most strongly implicated genomic regions to zoom in on the actual genes that increase MS risk. Breathtaking advances in molecular and statistical genetics, including the completion of the human genome sequence, give us the necessary tools to identify these MS genes. Understanding the genetics of MS will provide us with significant insights into the causes of disease and hopefully guide us to new treatment opportunities.
The Promising Future for MS Genetic Studies
Several
steps in the genetic dissection of MS must follow the current
work. The first is to try to weed out the false-positive results
from the genomic screens, by testing more markers within each
of these regions and testing more families. Based on the initial
genomic screening results, the most interesting regions for
further consideration are on chromosomes 3, 5, and 19. Potential
linkage to chromosome 19 was first reported by our group in
1993.
The next step is to take these confirmed regions and
narrow the likely candidate gene region as much as possible.
While this has been viewed as a very difficult task, several
new developments will simplify the problem.
New Molecular Resources
The goal of the Human Genome Project is to provide
the complete human DNA sequence. As a by-product
of this effort, complete (if still somewhat inaccurate) genetic
and physical maps have been generated for all the chromosomes.
Expressed sequence tags for the majority of human genes are
now available, although the known or predicted function of
these genes is still largely unknown. Thus for any candidate
region, many genes are now readily available for study. Within
the near future, complete gene sequences and intron-exon structures
will become widely available, greatly simplifying the candidate
gene search. In addition, new genotyping techniques, such
as single nucleotide polymorphism genotyping on silicon chips
may make gene mapping and identification even faster and more
accurate. The Duke CHG is a leader in the application of these
new techniques to human disease.
New Statistical Methods
One problem with the case-control
study design is that positive results can arise for disease
irrelevant reasons. To eliminate non-genetic influences, family-based
association methods have been developed. The most commonly
applied is the transmission-disequilibrium test (TDT) which
examines the frequencies of alleles transmitted and not transmitted
to children. This allows the use of single affected individuals,
but also requires sampling their parents. The power of this
simple test arises from its reliance on linkage disequilibrium,
which usually exists over only very small intervals (usually
less than 1 cM). Thus it is very complementary to standard
linkage analysis, where the effect is broad (up to 30 cM),
but its discriminative power over small regions is low. The
TDT is best applied to the candidate genes that will fall
within the critical regions. Large data sets of such TDT trios
(an affected patient and both parents) are currently being
collected by several research groups around the world.
The Duke CHG has played a significant role in expanding and
extending these new methods for application to diseases such
as MS.
Genetic Interactions
Virtually all genetic studies to date
have examined only a single gene/marker/region at one time
and yet we know that MS is influenced by multiple genes. It
is likely that these genes interact with each other, and perhaps
with environmental influences, to generate the MS phenotype.
These complex interactions can be examined by a number of
approaches. Thus future studies of MS will need to incorporate
both genetic and environmental information in their data collection
and analysis. The
Multiple Sclerosis Genetics Group is collecting this important
environmental information on their patients in order to examine
gene/environmental interactions.
Chromosome
19
Previous genetic studies have indicated a region on chromosome 19 near the APOE gene as containing a susceptibility gene for MS. We recently examined this region in detail in a large data set of multiplex (> 2 MS patients per family) US MS families. We were able to confirm our earlier findings of potential linkage and association in this are in a much la. In addition to our analysis of US MS families, we have recently studied a population of MS patients from San Marino, Italy. San Marino is a small somewhat isolated population with a high frequency of MS (1/1000). There is no HLA-DR2 association in these families. Thus, we performed a genomic screen on the San Marinese families and then analyzed these data using family based association methods. We identified seven regions exhibiting evidence of potential association with MS. One of the most interesting areas was the region on chromosome 19 previously identified in our studies in the US series of families. These data provide further evidence of a locus on chromosome 19 that confers susceptibility to MS. Efforts are currently underway to identify the chromosome 19 gene.
Exploring Chromosome 3
Another region under investigation is chromosome 3p21. There are two candidate genes of interest in this region, CCR5 and CCR2B. These genes are interesting because aberrant expression of the proteins coded for by these genes has been detected in instances of demyelination. We found that some MS patients carry a CCR5 allele with a 32 base pair deletion. These patients had an age of onset 3 years later than those patients without the deletion.
As CHG researchers continue to define the genetic causes of MS, they publish their findings in leading academic journals and share their knowledge with colleagues at meetings and conferences.
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MS Support Groups and Information Sources
The Multiple Sclerosis Genetic Group
National Multiple Sclerosis Society
733 Third Avenue
New York, NY 10017
Phone: (800) FIGHT-MS
Phone: (800) 344-4867
E-mail: info@nmss.org
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