Gene Mutation Can Increase Risk of Diabetes and Thyroid
Problems
Alterations to a key gene that helps regulate the immune
system can increase a person's risk of getting early-onset
diabetes or having thyroid problems, British researchers say.
The gene believed to boost risk if it has the variation is
the CTLA-4 gene, they report in the May 1 online issue of the
journal Nature.
"Only about 10 genetic associations in all of common disease
have been established," says John Todd, a professor of medical
genetics at the University of Cambridge. "And CTLA-4 can now be
added to the short list."
This variation is present in about half the population,
according to the researchers. The gene applies a kind of
"molecular brake" to stop the immune system from running amok
and causing autoimmune disorders -- diseases in which the body
turns on itself and attacks normal cells instead of attacking
invading organisms.
Before arriving at the conclusion, the researchers conducted
genetic studies in families. They found that a small region of
the human genome on chromosome 2 was home to three genes
associated with the immune response, and decided they would be
suspect candidates for contributing to the disorders. A mouse
model of early-onset (type 1) diabetes had already confirmed
that susceptibility to the disease was associated with the same
three genes.
When they analyzed the genes for small genetic variations,
they found that having the variants on the CTLA-4 gene increased
susceptibility not only to type 1 diabetes, but also to two
thyroid disorders -- Grave's disease, in which the gland
enlarges and overproduces thyroid hormone, and autoimmune
hypothyroidism, in which the immune cells inappropriately attack
the gland and make it underactive.
"The CTLA-4 gene has a very fundamental role in the immune
system regulation of the T lymphocytes' [a kind of white blood
cell that fights infection] activation and expansion," Todd
says. "T cell activity is central to all these diseases, and
hence a gene that has this critical effect on T cells will
affect many diseases," he adds.
While there is no immediate benefit from the new finding to
those already affected by the thyroid disorders or diabetes, the
hope is that the discovery will help experts target future
therapy or help identify those at high risk.
"Its a very important study in both immunology and human
genetics," says Michael Curran, a postdoctoral fellow in
immunology at the University of California at Berkeley. "It
shows that CTLA-4 misregulation can predispose to a variety of
autoimmune disorders."
It was already known, he adds, that absence of CTLA-4 can
cause problems, "but this study highlights that even minor
perturbations in the levels of expression of various forms of
CTLA-4 can have significant autoimmune consequences."
"The authors very convincingly show that a mutation in a
non-coding region of the CTLA-4 genes -- that is, a mutation
which indirectly affects the type or levels of the CTLA-4
protein that is produced, rather than one [a mutation] which
directly alters the coding sequence for the protein --
predisposes its bearers to Graves' and autoimmune
hypothyroidism. An association with type 1 diabetes is also
suggested but less strongly supported by their data," Curran
says.
The weakness of the study, Curran adds, is that while the
statistical linkage between these CTLA-4 mutations and disease
susceptibility are well proven, the biological mechanisms by
which the mutations increase risk "remain unproven and largely
speculative."
The significance of the finding? "Mapping risk factors for
multi-genetic disorders such as type 1 diabetes might allow you
to identify individuals at higher risk and give them preventive
treatment," Curran says. But he cautions that the treatment
would have to have minimal side effects and be deemed safe
first.
|