ROCHESTER, Minn. -- Why do women develop multiple sclerosis (MS) almost twice as often as men? Physicians have long been intrigued by this fact -- and now a Mayo Clinic-led international research team has identified a genetic variation that may explain it.
The report from collaborators in Minnesota, Northern Ireland, Belgium and Italy appears in the Jan. 27 online publication of the journal Genes & Immunity (http://www.nature.com/gene/).
Significance of the Finding
"In practical terms, this is what our findings suggest: How much of the protein known as 'interferon gamma' you produce appears to be a new key variable in understanding who gets MS and who doesn't, and especially why women develop MS more often than men," explains the study's lead author, Mayo Clinic neurologist Brian Weinshenker, M.D. "If you have a gene that produces high levels of interferon gamma, it may predispose you to developing MS. Under this scenario, men get MS less often because they have a lower frequency of a gene variant that is related to higher secretion of interferon gamma."
To researchers looking for a cure for MS -- where currently there is none -- the finding is helpful for three main reasons: 1) it provides a target at which to direct future investigations into ways to stop MS, 2) it provides leads on ways to improve treatments that can minimize the tissue and nerve damage the disease causes, and 3) it may advance the search for new treatments for other diseases. Notes Dr. Weinshenker, "Our finding isn't the whole genetic cause, but it's a helpful step that could lead us to a more complete understanding of MS -- and ultimately, effective treatment. It's also a very promising lead about gender differences that may pertain to susceptibility of other diseases, too, such as rheumatoid arthritis."
MS is a complex neurological disease of the covering of the brain and spinal cord that disrupts nerve transmission. It is caused by a combination of genetic factors -- there is not a single MS gene -- and is also believed to be influenced by various factors in the environment. MS is diagnosed in an estimated 400,000 people a year in the United States, according to the National Multiple Sclerosis Society (http://www.nationalmssociety.org).
The hallmark of the disease is the emergence of multiple areas of inflammation and scarring of the protective myelin sheath that covers nerve fibers. Symptoms include fatigue, weakness, balance problems, numbness and vision problems if the optic nerve is affected. Though it often evolves into a progressive disease, its severity varies widely. Some patients have few discernable symptoms, while others steadily lose mobility and may require wheelchair assistance to move.
The Mayo Clinic research group considers MS to belong to a group of diseases known as autoimmune diseases, in which the body erroneously attacks its healthy cells as if they were disease-causing foreign invaders. With MS, the body attacks tissues of the brain and spinal cord, creating scars that impair nerve signal transmission and lead to disability.
Interferon gamma belongs to a group of proteins that communicate with cells. Research by scientists at the Cleveland Clinic has shown that women and men naturally express different levels of interferon gamma. Experiments elsewhere showed that high levels of interferon gamma could intensify the MS damage processes and make the disease worse.
Combining these three lines of evidence -- 1) women get MS more often, 2) women have higher levels of interferon gamma and 3) high levels of interferon gamma worsen MS -- suggested to the Mayo Clinic research group that interferon gamma may play a role in driving the gender bias toward women in MS susceptibility. This would be especially true, they hypothesized, if a genetic variant existed that produced high levels of a kind of interferon gamma that tended to promote inflammation and tissue damage, the hallmarks of MS. If that variant were overrepresented in women compared to men, it would explain at least some of the excess risk of MS in women. Through sophisticated genetic analysis, this is exactly what the researchers found in the laboratory.
Then, in collaboration with researchers from Northern Ireland, Belgium and Italy, the Mayo Clinic group compared MS in four patient populations. They found that men have the gene variant that causes high levels of interferon gamma less often than women. Says Dr. Weinshenker, "It seems as if men have a lower frequency of high secretion interferon gamma genetic variant, and that might explain why men are generally protected more from MS."
Collaboration and Support
In addition to Dr. Weinshenker, research team members from Mayo Clinic include: Orhun Kantarci, M.D.; David Hebrink; Janet Schaefer-Klein; Mariza de Andrade, Ph.D.; Elizabeth Atkinson; Sara Achenbach; and Cynthia McMurray, Ph.D. Other researchers include Koen Vandenbroeck, Ph.D.; Colin Graham, M.D.; Stanley Hawkins, M.D.; and Shirley Haggerty from Belfast, Northern Ireland; An Goris from the University of Leuven, Belgium; and Maria Marrosu from University of Caligari, Italy. Grants from the National Institutes of Health and from the National Multiple Sclerosis Society supported the work.
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