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Asthma Drug Resistance Linked to Variant in Androgen Synthesis Gene

NEW YORK – A genetic variant associated with poor overall lung function also appears to coincide with poorer-than-usual response to glucocorticoid-based asthma treatment, new research suggests. The work reveals biology that may also hold clues to understanding responses to other asthma therapies.

"These findings provide us with important new information that may lead to more tailored treatments for asthma patients and the ability to prevent the development of severe disease," first author Joe Zein, a pulmonologist at the Cleveland Clinic's Lerner Research Institute and Respiratory Institute, said in a statement.

For a study scheduled to appear online this week in the Proceedings of the National Academy of Sciences, researchers at the Cleveland Clinic, Indiana University School of Medicine, and elsewhere tapped into genome sequence data for nearly 1,900 individuals with asthma, profiled for the Severe Asthma Research Programs (SARP), which are sponsored by the National Heart, Lung, and Blood Institute.

"Glucocorticoids, which modulate systemic inflammatory response, are commonly prescribed to treat severe asthma. However, until now we have not understood why many patients do not benefit from them," senior and corresponding author Nima Sharifi, a researcher and physician at the Lerner Research Institute, said in a statement.

The researchers' focus was on one gene in particular, a steroid hormone-related enzyme-coding gene called HSD3B1 that typically converts a compound called dehydroepiandrosterone (DHEA) from the adrenal gland to androgen hormones. Variants in the gene that seem to dial this conversion up or down caught their attention, since glucocorticoid treatment for asthma itself can mute adrenal androgens.

When the team genotyped HSD3B1 in 318 glucocorticoid-treated or non-glucocorticoid-treated asthma patients with available lung function measurements, it found that a missense variant that is linked to reduced conversion to androgen coincided with poorer-than-usual treatment response and reduced forced expiratory volume, a measure of lung function. In contrast, patients who carried two copies of a "permissive" HSD3B1 allele that is linked to increased conversion to androgen was not associated with reduced lung function.

"These data suggest that androgen depletion, whether circulating and/or at the tissue level, could contribute to the pathophysiology of severe asthma and resistance to oral [glucocorticoid] therapy," the authors wrote.

More broadly, Sharifi said, such results "make the case for genetic testing and personalized treatment and provide important information for identifying which patients should be treated using different therapies."

The researchers went on to verify such patterns with data for nearly 200 more asthma patients from other arms of SARP, before digging into the roots of this relationship further. They noted that the ties to glucocorticoid treatment response in asthma may also prove useful for understanding resistance to such treatments in other inflammatory conditions.

On the other hand, the study's authors noted that the allele they linked to poor lung function and diminished glucocorticoid response in asthma has also been associated with decreased adrenal androgen levels in prostate cancer, suggesting there could be additional consequences to tamping down adrenal androgen production with glucocorticoid therapy.

"Evidence that the adrenal restrictive HSD3B1 … allele, which confers a lower level of prostate cancer adrenal androgen dependence by preventing local conversion of DHEA to more potent androgens, adversely affects lung function in [glucocorticoid]-dependent severe asthma suggests that androgens have a central role in the pathophysiology of human severe asthma and response to systemic [glucocorticoid] treatment," they wrote.