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From Prediction to Prevention: The Long-Term Goal
Type 1 Diabetes Genetics Consortium Releases New Genetic Susceptibility Results

In the November issue of Diabetes, the Type 1 Diabetes Genetics Consortium (T1DGC), an international research collaborative, reports the identification of a variety of Human Leukocyte Antigen (HLA) alleles that were shown to be significantly associated with type 1 diabetes (T1D), the autoimmune form of diabetes. Researchers have been searching for decades to unravel the complex puzzle of which alleles of HLA and other genes are responsible for causing T1D, a disease in which the immune system attacks the insulin producing cells in the pancreas.

‘‘We still don't fully understand all the genetic components involved in disease susceptibility.”

"A T1D diagnosis used to be a death sentence, it was awful," says first author and CHORI scientist Janelle Noble, PhD, principal investigator of the North American HLA genotyping core for the T1DGC. "Now that we can treat T1D with insulin, it has become a controllable disease, but it is still a chronic condition with potentially life-threatening complications."

While genes in the HLA region of chromosome 6 have long been identified as the major players in T1D susceptibility, no studies have been large enough to both fully reveal the complexity of the association of the classical HLA genes with T1D and capture other genes in the HLA region that could contribute to disease susceptibility.

“Although we have had the technology to scan the genome available to us since the '90's, our studies were simply too small to accurately identify all of the genetic players that might be impacting T1D susceptibility.”
Two reasons that such large studies are required to capture genetic effects are 1) the effects of all non-HLA genes on T1D susceptibility are very modest, and 2) the high degree of linkage disequilibrium (LD) that occurs in the HLA region confounds efforts to sort out the susceptibility effect of any single gene.

"Linkage disequilibrium occurs when certain combinations of alleles at two genes occur far more often than would be expected by random chance, suggesting that some kind of selective pressure exists that keeps the pairs together," Dr. Noble explains.
"Let's say for example that whenever a person has allele "x" at gene "A," they also always have allele "y" at gene "F" riding along on the same chromosome because of LD. If you test patients with a particular disease for allele y at gene F, and all the patients have it, you think, hey, allele y at gene F is causing the disease. In fact, allele y at gene F may be just a hitchhiker, and the real disease causing gene is allele x at gene A. In other words gene F may have no real effect, but its alleles are in LD with alleles at gene A that have a strong effect."

As a result, teasing out what is really causing disease, and what is just coming along for the ride, is enormously complex, and requires very large sample sizes to confirm whether a particular gene is actually causing the association, or is simply along for the ride.

"The more research that was published from these smaller studies, the results of which often conflicted with each other, the more it became very clear that no one lab was going to be able to solve this question. DNA from that 300 familes, or even 700 families, just wasn't going to be enough," says Dr. Noble.

As a result, the idea was born to establish a worldwide group of researchers who could pool their resources to create a large enough study, which includes samples from thousands of families as well as individual diabetes patients and non-diabetic controls, to solve these larger questions of T1D susceptibility – and the results have been dramatic.

"We've known for a long time that the genes that encode the HLA-DR and -DQ antigens are the biggest players, but we've also known that they can't explain all the susceptibility, that something else must be going on," Dr. Noble says.

“What we were actually able to do in study is to show with good statistical power, that in addition to the class II alleles encoding DR and DQ, HLA class I-encoding alleles have an independent contribution to disease susceptibility.”

While many questions still remain regarding T1D susceptibility, the groundbreaking data from the T1DGC studies is taking researchers one step closer to identifying the root causes of T1D, and ultimately to the potential for intervention or prevention of this life-threatening disease.

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Tuesday, May 17, 2011 8:19 AM

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