Gene Variant Could Explain Why Asthma Treatment Often Fails

A new study has revealed a genetic variant among asthma patients who don’t respond well to steroid inhalers, the main treatment for the disease. The discovery could lead to a DNA test that could identify such patients early on, allowing doctors to prescribe alternative treatments instead.

As many as 40 percent of asthma patients don’t respond well to steroid inhalers. Prior to the new study, published today in the New England Journal of Medicine, researchers had been unsuccessful in their attempts to identify specific genetic factors associated with such patients’ response to the relevant class of steroid hormones, called glucocorticoids.

But now, for the first time, researchers have shown a link between a gene and decreased inhaler response. The researchers found that patients with the mutation were about 2.5 times more likely to respond poorly to inhaled glucocorticoids. Cell-culture studies showed that the mutation decreased expression of a gene found in lung and immune cells that contributes to asthma symptoms.

It’s unlikely that this mutation is the sole cause of impaired asthma drug response, but the finding renews hope that clinicians can use genetics to individualize treatment plans for asthma patients. “As we identify more of these genes, and this isn’t far off, we’ll be better able to tailor asthma treatments to patients,” says study coauthor Scott Weiss, a researcher at the Channing Laboratory, a research division of Brigham and Women’s Hospital and Harvard Medical School.

Personalized medicine has always been a goal of human genetics research. When the human genome was sequenced 11 years ago, many people assumed DNA-based drug response tests were right around the corner. But by and large, this hasn’t been the case. Genomewide analyses haven’t turned up as many candidate genes as expected, and results that seemed promising have proved difficult to replicate in follow-up studies.

Studying the genetics of asthma has been particularly challenging because the symptoms vary so much from patient to patient. “It’s probably not one disease, but several disease subtypes that look very much alike,” says Michael Kabesch, an asthma genetics researcher at the Hannover Medical School in Germany.

For the new study, the researchers took advantage of a large clinical trial conducted by the National Institutes of Health that carefully monitored children’s response to asthma treatments over five years. After they linked the genetic variant to reduced glucocorticoid response in those patients, the researchers replicated the findings in patients from three other clinical trials. Combined with the cell-culture work, this enabled the researchers to tie the mutation to asthma drug response.

Weiss and his colleagues suspect that whole-genome sequencing, which is just now becoming more affordable, will help identify other genetic variants involved with glucocorticoid response. They’re also conducting pharmacology experiments on cells from patients with the mutation. “We still have to figure out exactly what this gene does,” says Kelan Tantisira, a pulmonologist at the Channing Laboratory who coauthored the study. “Then we can work toward building these predictive tests.”