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.

International MS Genetics Consortium Successfully Launched

In 2003, a large international collaboration focused on the genetic dissection of MS was formed. It includes all the members of the MSGG research group as well as groups from Harvard University, the Broad Institute of the Massachusetts Institute of Technology (MIT), and the University of Cambridge in the United Kingdom. By bringing together many experts on MS genetics and combining some of the largest family data sets available in the US and UK with the most cutting-edge molecular-genetic and statistical resources from several institutions, we hope to accelerate the process by which we will gain more insight into the causes of MS. Visit their website to find out more information about the International MS Genetics Consortium (IMSGC)'s research goals and ongoing projects.

Multiple Sclerosis Study Participation

This study is a collaborative effort between many universities. The CHG’s role in the study is to do the laboratory and data analysis.

Our colleagues at University of California at San Francisco (UCSF) enroll qualifying families.

You can reach the UCSF study coordinator at
Phone: (toll free) 866-674-3637 ss
E-mail: msdb@itsa.ucsf.edu.

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CHG Multiple Sclerosis Publications

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.

Multiple Sclerosis Research Publications


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Additional Multiple Sclerosis Information

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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