Illinois University: Researchers
at the University of Illinois at Chicago have identified a genetic
variation that in women significantly increases their risk of developing
multiple sclerosis. The variant occurs almost twice as often among women with MS as in
women without the disease, making it “one of the strongest genetic risk
factors for MS discovered to date,” said senior author Doug Feinstein,
professor of anesthesiology at UIC and research biologist at the Jesse
Brown VA Medical Center. The report is published in the journal ASN
NEURO.
Feinstein and his colleagues were able to test three sisters among a
group of five siblings between the ages of 23 and 26, all diagnosed with
MS. They found the variant in all three they tested.
What they found was a genetic change known as a single nucleotide
polymorphism, or SNP – a change in a single base-pair of the DNA – in a
gene called STK11, which plays a role in tumor suppression and is
believed to have several roles in brain function.
MS is a neurodegenerative inflammatory disease that affects
approximately 2.5 million people worldwide. It causes damage to the
myelin sheath, which encases neurons like the insulation on a wire. Loss
of myelin interferes with the transmission of signals along the nerve
fibers and impairs motor function, including walking and speech.
Symptoms, which can be sporadic or progressive, range from mild to
debilitating.
Genetic factors are known to influence the risk of developing MS. The
UIC researchers were led to this variant thanks to a woman
participating in another study at UIC. In a casual conversation, the
woman told study coordinator Anne Boullerne that she and her four
siblings – three sisters, including twins, and a brother – all had
multiple sclerosis.
“This is an extremely rare occurrence,” said Boullerne, who
is research assistant professor of anesthesiology and lead author on the
paper. She said she could find no published studies with five siblings
with multiple sclerosis.
“I was immediately interested in the possibility of a genetic study
of the family because all five siblings – an entire generation – are
affected by MS, and so we could have a very good chance of discovering
key genes related to inheritance of the disease.”
The woman also described among her sisters and the women on her
mother’s side of the family a prevalence of diseases associated with
Peutz-Jeghers syndrome, a rare genetic disorder caused by mutations in
the STK11 gene and characterized by an increased risk for certain
cancers, including breast, ovary and colon cancers.
A literature search by Feinstein uncovered an article that described
how mice with a disabled STK11 gene had a higher incidence of loss of
myelin from the nerves of the central nervous system – a defining
characteristic of MS.
The woman consented to a complete DNA-sequencing of her genome.
Boullerne took a close look at the STK11 gene, where she discovered the
SNP. She next obtained consent to sequence the genomes of two of the
woman’s sisters and found they also carried the same SNP.
To determine if the SNP could be a contributing factor to the
siblings’ multiple sclerosis, the researchers screened DNA samples from
1,400 people – 750 with MS and 650 without – provided by Jorge Oksenberg
at the University of California, San Francisco, who is a leading expert
on the genetics of MS. They found that the SNP was 1.7 times as
prevalent in women with MS as in women without the disease, making it
one of the highest known genetic risk factors for MS.
Based on their analysis, the researchers estimate that the STK11 SNP
is present in about 7 percent of the general population. But because far
fewer people develop MS, other genetic or non-genetic factors must play
a role in the development of the disease, Feinstein said.
Feinstein and Boullerne plan to continue their hunt for other genetic
factors that may contribute to MS among the five siblings and possibly
their parents. They will also investigate the function of the STK11 gene
in the lab, which could reveal molecular pathways involved in multiple
sclerosis.
Other co-authors are Sergey Kalinin and Paul Polak, UIC research
associates in anesthesiology; Fernando Testai, UIC assistant professor
of neurology; Demetrios Skias, UIC assistant professor of neurology and
neurologist at the Jesse Brown VA Medical Center; and Elizabeth Hartman,
neurologist at the Center for Neurosciences, Orthopaedics and Spine in
Dakota Dunes, South Dakota.
This research was supported by in part by a Research Career Scientist award to Feinstein and by a grant from Biogen-Idec.
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