The hunt for genes involved in MS susceptibility moved one step closer to its goal when researchers at UMDNJ were able to narrow their focus to a specific region of chromosome 12. This finding resulted from investigations conducted by faculty at UMDNJ-New Jersey Medical School (NJMS) and was published in February's issue of the journal Human and Molecular Genetics. Three generations of a family of Pennsylvania Dutch extraction in which multiple members were diagnosed with MS participated in this genetic linkage study. Seven of 16 blood relatives examined and tested by the team had distinct evidence of the disease clinically and on MRI brain scans while nine had no evidence of MS.

Researchers have been pursuing the genetic causes of multiple sclerosis for decades and their work is beginning to pay off. The basis for a genetic link has been firmly established through prior studies.

Stuart Cook, MD, UMDNJ president and one of the study's investigators, says MS is a complex disease and that genes alone are not responsible, although genes clearly enhance susceptibility. He cites the environment as the second major factor. Data showing that migration influences risk for this disease supports this concept. "If you move from a high to a low risk area, or a low to a high, you can change your risk of developing MS or the risk of your offspring, although this is not always the case," he explains.

"There is a crude latitudinal relationship, with the risk for MS increasing the farther north you go in the Northern hemisphere," Cook continues. That rule of thumb does not hold for extreme northern latitudes and there are many exceptions, including Japan and China. "A similar but reverse pattern exists in the Southern hemisphere – with a higher risk of MS in southern New Zealand and Australia."

Infectious agents are the primary environmental suspects, among them canine distemper virus, Epstein Barr virus (that causes mononucleosis), herpes viruses and chlamydia pneumonia. The NJMS group has done extensive research on the animal-to-human link, specifically the agent that produces distemper in dogs. Cook comments that these agents can infect without producing major symptoms, and that many who have been exposed may not be aware of their infection. He believes MS to be an uncommon consequence of a common infection.

Finding a gene or multiple genes for a particular disease is a laborious and time consuming process which often takes many years. Identifying a family with several affected members and then discovering the genetic components they have in common can point investigators to the general site of the implicated gene.

According to Cook, there is one particular allele (one of a pair or series of genes) that has been associated with MS in many studies. This allele has been dubbed DR15DQ6. In the large family studied by the medical school team, all members with MS had this allele, but some individuals without evidence of the disease also had this allele.

This finding led to the next step of the investigation: Emilia Vitale, PhD, an NJMS genetics researcher on the team, tested the 16 participants for haplotypes associated with multiple sclerosis. A haplotype is a set of alleles that is closely linked on one chromosome and inherited together. All seven family members with the disease had the DR15DQ6 allele plus the same haplotype called 12p12. None of the other nine had both. According to the researchers, the result indicates that this haplotype is associated with MS in this family.

"The import of this finding is that it narrows the search for a gene, which may contribute to MS pathogenesis, and perhaps for other genes that may be implicated in MS," states Cook. "It could also lead us to insights into the mechanism of tissue injury in this disease, why some people are more susceptible to MS than others,why a particular therapy works and even to an infectious agent."

This discovery raises some important questions: How ubiquitous is this finding? Does it pertain only to this family or can it point the way to a greater understanding of MS? Cook explains that there may be multiple genes involved, but the biological processes causing the disease may be the same. He says that studies of other families with multiple cases of MS will help to determine if their finding is unique to this particular family or is shared by others.

Vitale has recently received a grant from the MS Society to try to find the gene, a project that could take years. There are thousands of genes on this locus, or segment of the chromosome.

The NJMS researchers are continuing their investigations on many fronts. Cook enumerates reasons to feel hopeful: "Over the last 10 years we've gone from no treatments to several effective, FDA-approved drugs for multiple sclerosis. Using sophisticated molecular techniques, many investigators are searching for environmental triggers of MS. If multiple sclerosis can be shown to be caused by an infectious agent, it may be possible to develop a vaccine that could prevent the disease. We are also learning how the immune system causes tissue injury; and we're refining our knowledge of genetic risks."

He points to the current clinical trials of drug therapies. "Pharmaceutical companies are spending a lot of money on drug trials," he says. "We don't have a drug that's curative, but we are testing drug combinations that may very well prove more effective.

"We can solve this disease. There are many pathways leading us there," he concludes.

The UMDNJ-New Jersey Medical School faculty who are members of this team are:
Emilia Vitale, PhD, Stuart Cook, MD, Rong Sun, Kavitha Subramanian, Marvin Schwalb, PhD, and Christine Rohowsky-Kochan, PhD.