Researchers have identified the first genetic variant that significantly boosts a person's chances of developing type 2 diabetes. The protein encoded by the gene may suggest new targets for diabetes drugs as it is part of a molecular pathway not previously tied to the disorder.
Despite more than a decade of effort, scientists had reliably linked only two to three human genes to type 2 diabetes, and none of them seems to play a big role in the disease (ScienceNOW, 3 January 2001). Several years ago, neurologist Kari Stefansson and his team at deCODE Genetics, in Reykjavik, Iceland, began fishing for a diabetes gene in a large Icelandic family in which many members had type 2 diabetes. Their initial analysis, reported in 2003, suggested a link between the disease and a genetic marker on the long arm of chromosome 10.
In the current study, the researchers homed in on the region. When they examined it with 228 molecular probes in 1185 Icelandic people with type 2 diabetes and 931 controls, they found that one type of short genetic sequence was significantly more common among the diabetics than the controls. The sequence is part of a gene that encodes a transcription factor, a protein that controls the expression of other genes. Collaborating with researchers in Denmark and at the University of Pennsylvania Medical School, the deCODE team replicated its results in separate Danish and American populations, showing that this same genetic variant was more common in type 2 diabetes patients than in healthy controls.
Overall, Stefansson says, having one copy of the genetic variant raises a person's risk of developing type 2 diabetes by 45%, whereas having two copies boosts diabetes risk by 141%. (PPARgamma, one of the previously discovered diabetes genes, only raises risk by about 25% per copy of the variant.) "This is the first genetic variant isolated that has a significant impact on the risk of type 2 diabetes," says Stefansson, whose team reported its results online 15 January in Nature Genetics.
In retrospect, the suspect transcription factor is a logical player in the disorder: It controls the expression of a gut hormone called GLP-1 that regulates blood-glucose levels, in part by stimulating insulin secretion in the pancreas. "They found a new physiological link with diabetes," says geneticist Phillipe Froguel of Imperial College London. "If it is true, it might be a breakthrough." However, Froguel warns, the researchers have yet to explain fully how the variant they found might bring about the disease. Still, says David Altshuler, a geneticist at Harvard Medical School, "the result is particularly valuable because the gene in question was not previously known to be important to diabetes." As such, he says, it "provides a new direction for research."