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 RESEARCH NEWS

 

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.


 

Copyright of Lee Chung Horn Diabetes & Endocrinology 2009