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The Slow but Steady Path toward Prevention
CHORI Scientist Provides Compelling Evidence Against an Association of Tumor Necrosis Factor and Lymphotoxin-alpha with Increased Risk of Type 1 Diabetes

In the December issue of the Journal of Human Immunology, CHORI scientist Janelle Noble, PhD and her colleagues provide compelling data to address the much debated question of whether or not two immunomodulators, Tumor Necrosis Factor (TNF) and Lymphyotxin-alpha, contribute to susceptibility to type 1 diabetes (T1D).

"All our data argue that the TNF and LTA genes are not contributing to diabetes at all," says Dr. Noble. "People who are saying that polymorphisms found in the TNF and LTA loci contribute may be just seeing the effects of linkage disequilibrium."

Linkage disequilibrium (LD) is a term in genetics that refers to the likelihood of two alleles on the same chromosome traveling together more often than expected by random chance.

"Let's say you have a string of beads representing the chromosome, with each bead representing an allele of a gene, and if you have a red bead, or red allele, in position 1, you're really likely to get the disease," explains Dr. Noble.

"Let's also say that there's high LD in the region, so that whenever you have a red bead at position 1, you always have a blue bead at position 2. If you only examined position 2, you would conclude that the blue bead contributes to disease, when it's really just coming along for the ride due to LD with the red bead."

In the case of T1D, several polymorphisms have been found in the TNF and LTA loci which have been rigorously investigated, with conflicting results. This may be due to the fact that both the TNF and LTA loci are found in the human leukocyte antigen (HLA) region of chromosome 6. The HLA loci are well known to be the strongest genetic contributors to T1D susceptibility.

"The TNF and LTA genes in question are smack in the middle of the HLA region," explains Dr. Noble. "You have to account for that, to determine if it's a blue bead coming along for the ride, or a red bead that has its own role. You have to make sure that any association you see is not just due to HLA alleles."

This is exactly what Dr. Noble and her colleagues set out to do in the latest study which resolves, at least for Dr. Noble, just what color beads TNF and LTA are.

"What made our study different than the others is the way that we very carefully adjusted for the surrounding genes in our analyses," Dr. Noble explains. "We didn't just look at this gene as if it were in isolation. We looked at in the context of where it sits in the chromosome and what the other genes around it are doing."

In addition, Dr. Noble and her lab had all of the HLA data on the samples they were testing, and thus were armed with a much larger amount of information that has not been available in most other studies. Dr. Noble also had a bigger sample size than many of the other studies, and that allowed her and her colleagues to look at certain subsets of the samples of samples as well.

The end results were significantly revealing.
"At face value, our data looked like we really were seeing an association at first," says Dr. Noble. "But when we adjusted for LD, the two alleles that were apparently associated with T1D completely lost significance, and the allele that did not originally appear associated was now significantly associated. It was a complete flip-flop in results."

Upon looking more closely, Dr. Noble realized that this new association could be accounted for by the fact that the allele sits on a high-risk chromosome, but that the allele itself is not what makes the chromosome high-risk.

In addition to concluding that theTNF and LTA alleles are merely blue beads coasting alongside the red ones that really result in increased risks for T1D, the publication goes further to emphasize the importance of assessing LD in any genetic study, but in particular in T1D.

"Things are not always what they seem," Dr. Noble says. "You really have to be careful in how you analyze and interpret the data, because it's really easy to to come up with the absolute wrong conclusion."

After all, studies like this one are not conducted in the isolation of the basic laboratory, but with the ultimate goal of being able to predict who will develop T1D and who won't.

"You can't prevent unless you can predict," says Dr. Noble.

A critical step toward the ultimate goal of diabetes prevention, this study is the first of a series of analyses born from Dr. Noble's participation in the international Type 1 Diabetes Genetics Consortium, in which scientists are hard at work classifying and characterizing diabetes world-wide, in nearly 5,000 families of every ethnicity.

"The Consortium," says Dr. Noble, "represents the next - and we hope final - end-all, be-all study to figure out all the different candidates in the whole genome that confer risk in T1D."

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Monday, May 16, 2011 11:33 PM

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