Jim

In 2007, the International MS Genetics Consortium, which the National MS Society helped to create, published the results of a trailblazing study in which they analyzed 3,000 genetic samples — from 1,000 people with MS and their parents — in a quest to identify what they all had in common, gene-wise.

Now the consortium has spawned two sub-groups, one based in England and one in the United States, which will take the next steps: two mammoth studies, each scrutinizing the DNA of 10,000 people who have MS and 10,000 who don’t. That’s a total of 40,000 samples, half to be collected in Europe and half in America. Since the first study of 3,000 samples involved the analysis and interpretation of more than 1.5 billion data points, another 12 billion data points are expected. All of them need to be examined to identify new risk factors in MS.

The Wellcome Trust is funding the European side. The National MS Society is soliciting donations for the American part, which is expected to cost about $3 million. If successful, the work could result in earlier diagnosis of MS as well as individualized treatments that hone in on a specific patient’s needs.

“If there was a genetic variation in certain individuals with MS, then you could create a therapy that would target against that,” said Patricia O’Looney, PhD, the Society’s vice president of biomedical research.

“It’s not just wishful thinking; it’s reality. There’s a small clinical trial that is already targeting one of these genetic variations that was identified as a possible risk factor in MS,” she added.

There are two reasons this work is possible, one technological and one human. In 2001, the Human Genome Project led to the advent of an improved gene chip — a special computer processor used in genetics studies — capable of analyzing 500,000 genetic markers simultaneously. Then in 2003, Harvard researcher David A. Hafler, MD, won the Society’s Palmer Collaborative Center Award and used it to draw more than a dozen of the world’s leading geneticists into the MS movement.

Why two huge studies instead of one? “When you do a large study like this, it’s always important to do a validation and replication study,” O’Looney said. “If something comes out of the Wellcome Trust but doesn’t get replicated, it will be meaningless.”

The fact that the U.S. team is backstopping the British team in no way makes its work less important, O’Looney said. Dr. Hafler’s vision of a global scientific community pooling time and talent to shake loose the genetic secrets of MS only grows.

The genes a person inherits help determine whether that person is at increased risk for developing MS. While there is evidence from studies that this genetic component exists, it appears to be only one factor among several that determine who gets MS. Most likely, an individual’s genetic blueprint ultimately determines if that individual will be susceptible to a triggering factor in the environment, which in turn initiates the autoimmune process that leads to the development of MS.

Epidemiologic surveys have determined that an individual's risk of developing MS increases several-fold if a close family member has MS. While the average person in the United States has about 1 chance in 750 of developing MS, the risk for a person who has a parent or sibling with MS increases to about 1 in 40. MS. Thus, the risk increases significantly for a person whose parent has MS, but still remains relatively low.

These risk estimates, however, are oversimplifications that can easily be misinterpreted. We now know, for example, that risk estimates can vary greatly depending upon the structure of a person’s family. In families in which MS occurs in many relatives, the risks for any given individual are significantly higher than they are for an individual who has no family members with MS. Risk for MS is also affected in part by a person’s ethnic background and other factors that haven’t yet been clearly identified.

How do we know that genes are not the only factor in determining who gets MS? The identical twin of a person with MS has a 1 in 4 chance of developing the disease. The fact that identical twins of people with MS—who share all the same genes—don’t always get MS, and that more than 80% of people with MS do not have a first-degree relative with MS, demonstrates conclusively that MS is not directly inherited and that factors other than genetics must be involved.

In the past few years, scientists have developed a set of tools that give them the ability to pinpoint the genetic factors that make a person susceptible to MS. These tools are the methods of molecular genetics—techniques used to isolate and determine the chemical structure of genes.

In the 1980s, scientists began to apply the tools of molecular genetics to human diseases caused by defects in single genes. This work led to major advances in understanding diseases such as Duchenne muscular dystrophy and cystic fibrosis. The situation for diseases such as multiple sclerosis is more complicated. Scientists now believe that a person is susceptible to multiple sclerosis only if he or she inherits an unlucky combination of numerous genes.

Advances in molecular genetics and the identification of large families in which several members have MS—“multiplex” MS families—have facilitated scientists’ efforts to uncover MS susceptibility genes. Since 1991, the National MS Society has supported an international project searching for these genes. The research teams have the challenging task of finding an unknown number of genes that confer susceptibility to MS. This requires searching the 3.2 billion DNA bases that form the code of the 30,000 to 40,000 genes that make up the human genome.

Many multiplex families from throughout the world have agreed to participate in these studies. The researchers are looking for patterns of genetic material that are consistently inherited by people with MS. These recognizable patterns are called “DNA markers.” To do this, scientists probe the DNA of white blood cells from multiplex families searching for identifiable patterns or markers in the DNA code inherited in common by the individuals with the disease but absent in their healthy relatives.

When one of these markers is identified, scientists focus on that area, seeking additional markers closer to that gene. Eventually the location of that gene can be identified. This process of moving closer to the gene until it is identified has to be repeated for each of the marker regions from the multiplex families. By 1996, as many as 20 locations that may contain genes contributing to MS were identified, but no single gene was shown to have a major influence on susceptibility to MS

In 2003, Drs. David A. Hafler (Harvard Medical School and Brigham and Women’s Hospital) Stephen Hauser (University of California, San Francisco) and Eric Lander (Broad Institute of MIT and Harvard) jointly received the Palmer Collaborative MS Research Center Award: MS Targeted Haplotype Project from the National MS Society to pool expertise and resources in attempts to speed work toward discovering MS genes. This award propelled the formation of the IMSGC, a collaborating group of investigators with expertise in genetics, database design/construction, and clinical assessment and immunology of MS. This group includes Drs. Alistair Compston and Stephen Sawcer (University of Cambridge), Drs. Jonathan Haines (Vanderbilt University) and Margaret Pericak-Vance (University of Miami) and Dr. Jorge Oksenberg (UCSF). They have established a shared DNA repository, which enables them to gather the large amounts of data necessary to conduct genetics studies.

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.

The IMSGC’s 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 papers published online July 29, 2007 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. 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.

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.”

* Information included in this newsletter is gathered from a variety of sources. Jim claims no responsibility for the accuracy of information ...

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