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Type 1 Diabetes Susceptibility: Putting the Pieces Together
CHORI Helps Lead International Diabetes Collaboration

"People have been studying HLA and diabetes since the 70's and we still don't have it all figured out because it's so complicated," says Dr. Noble.

For decades, researchers have been trying to solve the puzzle of type 1 diabetes (T1D), a genetic disorder that causes the body’s immune system to attack the cells that produce insulin. In the May issue of Diabetes, CHORI scientists Henry Erlich, PhD, and Janelle Noble, PhD, along with their colleagues from the international Type 1 Diabetes Genetics Consortium, provide the first analyses from worldwide data gathered over 5 years that could at last provide the keys to the genetic susceptibly to T1D.

“When you have a single gene disorder, such as cystic fibrosis or sickle cell disease, there’s a single gene with a mutation in it that causes the disease,” explains Dr. Noble. “Diabetes, unfortunately, is what’s called a multigenic disease, in which many genes contribute to disease susceptibility, and different patients have different susceptibility.”

Although the HLA region has long been identified as a key genetic contributor to T1D, responsible for at least half of genetic susceptibility to T1D, there are six classical HLA proteins, some with over 1000 variants. That doesn't even include the non-HLA genes that contribute to T1D genetic susceptibility, creating a puzzle with a staggering number of different pieces.

Researchers traditionally tackle those different pieces by comparing polymorphisms - naturally occurring genetic variants - found in T1D populations with those found in healthy controls.

"With single gene disorders, this can be very straightforward," Dr. Noble says. "If you looked at patients with sickle cell for example, all your patients would have the hemoglobin mutation, compared with none of your controls. But in a complex disease like T1D, you might see 50 percent of patients have a variant, compared with 40 percent of controls."

The problem becomes that in order to confirm that the particular polymorphic difference is really related to T1D, and not just a sampling bias, researchers need a large enough number of patients. Unless a gene has a very strong effect, an individual researcher can have difficulty gathering a large enough sample to see that effect with confidence.
"Imagine flipping a penny 3 times and having it come up heads each time. Could you be sure that it came up heads each time because something was wrong with the penny? Now, imagine having flipped it 3000 times, and ti coming up heads each time.
In that scenario, Dr. Noble says, the probability that it was just random chance every time would be very, very small. The accepted value for calling an effect significant is a probability, or "p value" of 0.05.

"That means there's a 95 percent chance that the results of your study are not random, but truly influencing some aspect of genetic susceptibility," Dr. Noble continues. "But there's still a 5 percent chance that you didn't flip the penny enough times."

Not any more. The Type 1 Diabetes Genetics Consortium heralds a new beginning in diabetes genetics research, and the potential to finally put all the pieces of the puzzle together, with CHORI helping to lead the charge through its participation as one of 3 T1DGC HLA genotyping centers in the world.

While there are hundreds of clinical sites all over the world collecting samples for the T1DGC, CHORI represents one of only 3 HLA genotyping centers: one in North America (CHORI and Roche Molecular Systems), one in Europe (Malmö, Sweden), and one for the Asia Pacific network (Melbourne, Australia).
"Once we do the individual genotyping for each of the samples for which we're responsible, we upload the results to a central database for analysis," Dr. Noble explains.

As a result, CHORI has been able to help create the largest data set in history for T1D. After over 5 years of data collection, the consortium has met its goal of gathering data from over 4600 families in which at least two siblings had T1D.

"It used to be that each individual researcher would do their small studies and try to publish before somebody else. But with our worldwide effort, now we're all working together. We've learned that we can find out a lot more by pooling our resources."

"With these kinds of numbers, the consortium data takes the probability that what's being observed is a real result and not a random sampling effect from a 95 percent chance to a 99.9 percent chance," says Dr. Noble.

With the first publication based on consortium HLA data now out, previous studies with smaller samples sizes have already been replicated and confirmed, providing that much greater confidence in the accuracy of the results. In addition, the robustness of the data set provides the opportunity to really look at the contribution of genes other than those in the HLA region.

"We don't have a cure yet, and we don't have prevention yet, but it's close, it's going to happen. That means we have to be able to identify who is going to get the disease so we know which patients would benefit most from interventions," says Dr. Noble.

CHORI and the Type 1 Diabetes Genetics Consortium take researchers one step closer to doing just that, by providing the potential to finally complete the T1D susceptibility puzzle at last.

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Tuesday, May 17, 2011 8:19 AM

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