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Opening the Door to Prevention
New Study Confirms Association between the TNF(-308) Promoter Polymorphism and Stroke Risk in Children with Sickle Cell Anemia

Sickle cell disease (SCD) is the most common cause of childhood stroke, with a two- to three-hundred fold greater risk of children with SCD having stroke as compared to the general population. A variety of stroke studies in SCD populations have been searching for clues to this increased risk but – until now – have provided conflicting results.

For the first time, CHORI clinical scientist Carolyn Hoppe, MD, and her colleagues have confirmed in a replication study the association of a greater than three-fold increase in risk of stroke with the TNF(-308) G allele.

"Unlike family-based pedigree research studies, association studies have issues with control populations and it's very easy to get spurious results or false positives," explains Dr. Hoppe. "Replicating the results in an independent population as we have done here overcomes potential biases and provides much more powerful outcomes."

The outcomes of this study are particularly powerful for a number of reasons. The first is that the data comes from a diverse population.

Dr. Hoppe's initial study utilized data gathered from children participating in the Cooperative Study of Sickle Cell Disease (SSCD), which was designed as natural history study and followed 4,000 sickle cell patients at 10 different centers across the country while the replication study utilized data from the Stroke Prevention in Sickle Cell Anemia (STOP) trial.

As Dr. Hoppe says, "You're getting patients from all over the U.S. From a national standpoint, you're seeing results from Oakland, California patients and patients in New York City, and patents in satellite clinics in more rural areas in the south."

The second reason that the outcomes are so significant is that both studies used relatively small populations, yet still yielded statistically significant associations. Most association studies draw on data gathered from thousands and thousands of individuals in order to increase the strength of the conclusions. Because sickle cell anemia effects comparatively smaller populations, however, those kinds of numbers simply aren't available in the United States.

"The fact that we had such a big odds ratio with such a small population, and that the results were then replicated suggests a very significant association," says Dr. Hoppe.

The significance of the results opens a doorway into further research into the functional importance of the allele and its effect on the pathophysiology of sickle cell that could ultimately reveal a potential targeted therapy in the treatment or prevention of stroke. The information has a more immediate use, however, as a predictor with which to classify patients into different risk groups.

"The immediate relevance of this is that when we're looking to treat patients with sickle cell, our first question is, how severe will their disease be?" says Dr. Hoppe. "There's no way of knowing the answer to that when you've got a newborn in front of you. If we know up front that they're at risk, however, then we can say this person could benefit from treatment earlier."

Differentiating higher risk patients from lower risk patients is important because although there are preventative treatment options available for stroke - chronic transfusion or bone marrow transplantation - both come with potential risks as well. Regular blood transfusions cause iron overload that can damage the heart and liver, and requires patients to undergo subcutaneous chelation for up to 8 hours a day, while graft versus host disease is one of a handful of potential complications of transplantation.

"We do everything we can to screen for disease complications before they becomes much more difficult to treat," Dr. Hoppe explains, "but it would be invaluable up front if you had some way of determining a patient's risk for certain complications based on a profile of risk factors like the TNF allele, so that we can be more or less aggressive in our treatment."
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Monday, May 16, 2011 11:33 PM

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