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New gene linked to juvenile diabetes
By Bijal P. Trivedi

Inspired by clues from a mouse model of type-1, or juvenile, diabetes, Australian researchers have now identified a genetic variation in humans that increases susceptibility to the disease. Understanding how the interleukin-12B gene is linked to diabetes may eventually lead to new therapies.

Testing DNA from 249 pairs of siblings revealed that type-1 diabetics tend to share genetic markers on chromosome 5, close to the IL-12B gene. When Grant Morahan, of the Royal Melbourne Hospital in Victoria, Australia, and his colleagues sequenced the IL-12B gene they found two polymorphisms: a single base change at the end of the gene (IL-12B 3' UTR) and another variation in the regulatory region of the gene.

To determine whether these gene variants were common to diabetics, the researchers screened 238 families from the Australian diabetes DNA Repository. Morahan found a significant link between IL-12B 3' UTR and family members with diabetes. The results of the study are published in the current issue of Nature Genetics.

Human and mouse data converged when the Australians discovered that human cell lines with IL-12B 3' UTR variation produced higher quantities of IL-12. In diabetes-prone mice, IL-12 accelerates the onset of diabetes by stimulating the immune system to attack the pancreatic cells, but IL-12 inhibitors delay the onset of the disease if the animals are treated from three weeks of age onward.

"If the cell line results are true in people, then reducing IL-12 might be a way to reduce the chance of developing diabetes," says Morahan.

Other researchers dispute whether the therapeutic or diagnostic implications of this finding are clear. Modifying the levels of IL-12 may not be so simple because IL-12 has many functions in the body, says David Owerbach, a researcher at the Baylor College of Medicine, in Houston.

Owerbach thinks a more complex problem is that genetic variations that increase the risk of diabetes in one person may not affect other individuals in the same way. Even if the IL-12B 3' UTR polymorphism does elevate IL-12, it may not have much use as a diagnostic tool for identifying potential type-1 diabetics because the variant is very common in the population, he says.

Tracking down the cause of T1D is a challenge because the disease is influenced by up to 30 genes and a range of environmental factors, says Owerbach. IL-12B is only the third gene implicated in the disease, and it will be a while before the significance of this discovery is known.

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Morahan, G. et al. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet 27, 218-221 (February 2001).

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