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Considering Context: Diabetes Susceptibility
New Type 1 Diabetes Study Shows Genotypes Influence Susceptibility

"With T1D you can't look at genes in isolation. A gene isn't functioning in a vacuum, but in the background of all these other genes in the cell."

In a study highlighted in the June issue of Human Immunology, CHORI scientist Janelle Noble, PhD, and her colleagues uncovered some intriguing new clues to the ongoing mystery of type 1 diabetes (T1D) susceptibility.

“The most exciting result we found was that a certain chromosome which is known to confer high risk for diabetes seems to have a different effect on susceptibility depending on what genes are on the other chromosome,” says Dr. Noble.

The search for the genetic basis of T1D susceptibility has been on for decades, but has been complicated by the fact that T1D is a multigenic disease in which many different genes contribute to susceptibility, rather than just a single gene. Significant gains are being made as a result of an international collaboration, the Type 1 Diabetes Genetics Consortium, or T1DGC, for which Dr. Noble serves as a principal investigator for the North American HLA genotyping laboratory. Even with the large Consortium study, smaller, however, population based studies still have an important role to play.

"While the larger data sets we now have with the Consortium study are critically important, there is still a lot of value to the smaller studies looking at different populations. Sometimes effects that are seen in smaller studies are overlooked in larger ones," explains Dr. Noble.

"In this study, the result we found had been overlooked in earlier larger studies. The data from this small, focused study has pointed us in the right direction to look at a larger data set and ask the same question."

In fact, in a genetic study, it's more likely that meaningful results can be found the more homogenous the population is, which is why Dr. Noble and her colleagues went to such trouble to identify a matched set of patients and controls in continental Italy with homogenous genetic profiles.

“With only 133 patients and 162 controls, it looks like a tiny little study, but we screened over nine thousand samples to get those controls," Dr. Noble says. "Not many people in continental Italy have the high risk profiles we wanted to compare, and when you’re looking at genetic susceptibility to any disease it’s very important to have the controls and patients extremely well-matched."

Without such precise matching, comparing results in patients to those in controls could yeild incorrect conclusions, as the genes which cause diabetes in Caucasians, for example, may not be the same genes that cause the disease in African Americans.

In this case, Dr. Noble and her colleagues were looking for very specific risk categories in the human leukocyte antigen (HLA) region, which has long been identified as being responsible for nearly half of all genetic susceptibility to T1D.
"We only looked at three different categories of the highest risk HLA genotype, and we compared them to high risk control samples to ask the question, why did one set of subjects end up with diabetes while the other set didn't?"
The investigators only looked at individuals who had HLA chromosomes known as DR3 or DR4. Each person has two HLA chromosomes, so the study subjects had one of three possible genotypes, DR3/DR3, DR3/DR4, or DR4/DR4.

"DR3 chromosomes come in a number of different types, and a particular one we call 8.1 had very different effects on type 1 diabetes risk depending on whether we looked at it in the DR3/DR3 patients and controls or in the DR3/DR4 patients and controls," says Dr. Noble.

That genotype context could influence disease susceptibility so strongly underscores just how nuanced T1D susceptibility is, and just how diligent researchers must be in their search for the genetic underpinnings of the disease.

"The point is that people tend to look at just one gene and they look at it as just one locus or one chromosome,' Dr. Noble explains. "What our research says is that you have to look at all the genes and consider the context of both chromosomes. Risk is going to vary depending on what's on that other chromosome."

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Tuesday, May 17, 2011 8:19 AM

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