Gene dictates asthma severity

A child dies from malaria every 90 seconds, with overall deaths totaling almost three million per year. But the cytokines, or hormones, that control the inflamatory response which often kills malaria sufferers have now been found to play a central role in asthma.

While studying the role of a particular cytokine in malaria, macrophage migration inhibitory factor, Dr. Richard Bucala, professor of internal medicine at the Yale School of Medicine, and collaborators found that MIF expression determines asthma severity. This serendipitous correlation may help the 20 million Americans living with asthma find more effective treatment.

The study, published in the Proceedings of the National Academy of Sciences this month, showed that mice without the MIF gene had reduced asthma. Additionally, in 151 white subjects, low MIF expression had a high correlation with mild asthma.

“This gene doesn’t affect whether you get asthma, but rather the severity once you have the disease,” Bucala said.

Five years ago, Bucala’s lab discovered that humans have different versions, or alleles, of the MIF gene that contain five to eight repeats in the gene’s promoter. The more repeats, the more MIF produced. People with five repeats experienced only mild asthma.

Dr. Christopher Randolph, an asthma and allergy specialist, said this work offers alternatives to the standard inhaled steroid treatment.

“This research introduces a very clever model with tremendous merit and excitement,” Randolph said. “More work like this needs to be done to explore the genetic pathways, and then apply it to humans.”

While there is strong evidence supporting the MIF gene’s role in asthma severity, Bucala said environment can play an equally large part. Additionally, he said most complex traits are controlled by several genes.

“It is not likely one gene will explain the whole disease, but [this research] is so intriguing because it potentially provides a novel therapeutic approach, not just a genetic linkage.” said Dr. Paul Noble, a medical school professor in the pulmonary section.

However, Bucala theorized that selective pressure may be behind the proportions of MIF alleles in different populations. For instance, he said the MIF gene in Africa may protect against malaria and tropical infections. This could explain why 78 percent of Zambians have five repeats, and only 45 percent of white subjects from North America have that number of repeats.

“The MIF gene may protect you from some things and predispose you to others,” Bucala said. “You never know when a gene that may mean good news for one disease may mean bad news for another disease.”

High-repeat MIF alleles also have been linked to severe autoimmune arthritis, he said.

As a researcher of malaria, which predominantly plagues poor countries, Bucala said scientists are charged with creating solutions from their research. In a related project, his team developed an optical sensor biochip that reveals a patient’s MIF expression at low cost and with no instrumentation.

“You can’t just do first-world science in third-world countries,” Bucala said.

Bucala’s research group is currently testing a hypothesis that certain MIF alleles lead to death from malarial infection. If the detection chip is effective and the theory holds true, he said physicians can take preventative measures in high risk cases. Bucala and his team just returned from Zambia, where they studied the role of the MIF gene in a pediatric field hospital.

His lab has produced monoclonal antibodies which may neutralize high MIF expression for Baxter Healthcare. This line of therapy is currently in clinical studies for eventual application in reducing asthma severity.

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