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Looking to Centenarians for Sickle-Cell Answers

Why does the disease plague some and leave others unscathed?


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Click on the above slide show to hear Martin Steinberg, MED professor of medicine and pediatrics, explain his genetics research on sickle-cell disease.

We have much to learn from our elders, including, potentially, a better way to treat sickle-cell disease, according to a team of Boston University scientists.

Sickle-cell disease, a red-blood cell disorder prevalent among African-Americans, is caused by a single genetic mutation. But unlike many diseases, sickle-cell leaves some people with the mutation relatively unscathed, while afflicting others with complications such as heart disease, stroke, hypertension, and chronic pain, all of which contribute to a median survival among those with the disease of about 45 years.

Learning why it works that way is the quest of four Boston University researchers — Martin Steinberg a School of Medicine professor of medicine and pediatrics and director of Boston University’s Center for Excellence in Sickle Cell Disease, Paola Sebastiani, an associate professor of biostatistics at the School of Public Health, longevity researcher Thomas Perls, a MED associate professor of medicine and director of the New England Centenarian Study, and Clinton Baldwin, MED professor of pediatrics. In a research project backed by a three year, $6 million grant from the National Heart Lung and Blood Institute, part of the National Institutes of Health, they are looking for common genetic variations in people with sickle-cell disease who live longer with less severe symptoms and healthy people who live to be at least 100 years old.

The collaboration began about a year and a half ago, when Sebastiani was helping Steinberg investigate the genetic variations, known as single nucleotide polymorphisms (SNPs) associated with the different complications of sickle-cell disease. At the same time, Sebastiani was analyzing genetic data from Perls’ centenarians in a separate study, looking for SNPs associated with longevity.

“I started seeing some of the same genes showing up in both analyses,” says Sebastiani, citing an observation that jibed with the fact that many complications of sickle-cell anemia are also age-related diseases. “It’s possible,” she says, “that we could look at sickle-cell anemia as a model of accelerated aging.”

If Sebastiani is right, that would mean that many of the same genetic variations that protect against aging could also mitigate sickle-cell complications. To test this hypothesis, Sebastiani, Steinberg, Perls, and Baldwin have been searching for SNPs that are strongly correlated with both sickle-cell patients who outlive the norm and with the extremely long-lived subjects of the centenarian study. To do that, Baldwin processed blood samples from thousands of centenarians in Perls’ study and from sickle-cell patients from Steinberg’s center in a machine that searches for hundreds of thousands of SNPs in each person’s DNA. While the genotyping will be wrapped up this summer, more complete analyses of such a vast assortment of data will take much longer, and may continue for years. The good news is, Steinberg reports that preliminary findings “suggest that there might be genes affecting vascular function that are common in predicting exceptional longevity and survival in people with sickle cell anemia.” They expect to have more definitive results as early as this fall.

A better understanding of which genes moderate the severity of sickle-cell disease will allow doctors to analyze the DNA of people with the disorder early on, and weigh the usefulness of pursuing side-effect laden or risky treatment options. A strong genetic connection between long-lived people with sickle-cell disease and centenarians could also give researchers a head start on where to look for other genes associated with longevity, genes that are notoriously difficult to identify. Eventually, say the researchers, these genes may become targets for the development of drug therapies for the complications associated with sickle-cell anemia.

In the meantime, Steinberg and his fellow researchers are enlisting new patients for more DNA analysis. “Whenever you do this type of work that involves a lot of genotyping, it needs to be validated in new populations,” he says.

Chris Berdik can be reached at cberdik@bu.edu.

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