Genetic Study Opens the Door for Treatment of Glucocorticoid-Resistant Asthma

The ability of glucocorticoids (GC) to modulate systemic inflammatory response makes these hormones indispensable for the treatment of severe asthma. Yet for unknown reasons, many asthmatic patients do not respond to GC treatment.

An interdisciplinary team of clinicians and researchers appears to have uncovered the reason for this lack of response: A variant of the gene HSD3B1 known as HSD3B1(1245A), which is associated with poor lung function and GC treatment resistance.

The finding has exciting implications for 50% of patients, whose asthma remains uncontrolled.

“This variant may be helpful in identifying patients who are unlikely to respond to GCs and more likely to need a different treatment,” says Cleveland Clinic pulmonologist Joe Zein, MD, first author of the study published in Proceedings of the National Academy of Sciences.

Effects revealed

To reach this finding, Dr. Zein and colleagues analyzed the association between genomes and pulmonary function in more than 500 patients in the Severe Asthma Research Program (SARP) III cohort treated with and without GCs.

Androgens are thought to have an anti-inflammatory effect that might be beneficial in asthma. While the HSD3B1 gene encodes an enzyme that converts adrenal dehydroepiandrosterone (DHEA) into more potent androgens, the researchers discovered that the HSD3B1(1245A) variant limits the conversion. Conversely, the HSD3B1(1245C) allele increases DHEA conversion to androgens.

Subsequently, they explored the association between DHEA and percentage predicted forced expiratory volume in 1 second (FEV1PP). “GC patients homozygous for the adrenal restrictive genotype had lower FEV1PP, compared with patients who did not take GCs. This suggests the variant contributes to resistance and helps drive progression to severe asthma,” Dr. Zein explains.

They validated these findings in the SARP II cohort.

This was the first study to provide genetic evidence suggesting variants related to androgen synthesis affect treatment resistance in asthma.

Clinical implications

“Precision medicine in asthma is based on anti-IL5, IgE and type 2 inflammation. However, the greatest risk factor is being female,” says Dr. Zein.

Indeed, 60 to 80% of patients presenting to the emergency department with exacerbations of asthma are women, and mortality in adult women is double that in adult men.

“We have to understand why asthma is worse in women. I felt we needed to look into the potential role of hormone therapy in women with asthma,” says Dr. Zein.

DHEA supplementation has been shown to benefit patients with chronic obstructive pulmonary disease and pulmonary hypertension in small trials. Dr. Zein and colleagues postulated it might also benefit asthmatic women with low DHEA levels.

To test this theory, they conducted a pilot study of 16 premenopausal women ages 18 to 50 with mild or moderate asthma and gave them 100 mg DHEA orally every 12 hours for two weeks. Spirometry and serum DHEA (DHEAS) were measured at the initial visit and conclusion of the treatment.

In those with low starting DHEAS (less than 200 mg/dL), levels increased from 71 ± 23. Post-albuterol FEV1 correspondingly increased by 51 mL, from 3.026 ± 0.5 to 3.077 ± 0.49 L.

In those with high starting DHEAS, the increase in circulating hormone was smaller, and post-albuterol FEV1 did not change significantly.

“These preliminary results suggest that over-the-counter DHEA may improve lung function in women with asthma and low DHEAS levels,” says Dr. Zein. “However, any recommendation regarding the use of DHEA will require a randomized, controlled clinical trial.”