Glucocorticoids (GC), which modulate systemic inflammatory response, are commonly prescribed for the treatment of severe asthma. While it is not currently understood why, it is recognized that many asthmatic patients do not respond to GC treatment and must be treated using different therapies.
In a new study published in Proceedings of the National Academy of Sciences, an interdisciplinary team of researchers led by Nima Sharifi, MD, Department of Cancer Biology, uncovered a possible genetic explanation for this resistance, identifying a novel gene variant that is associated with GC treatment response and may be clinically useful to help identify patients most likely to benefit from alternative treatment strategies.
Previous research has shown that systemic GC treatment can result in the suppression of endogenous adrenal androgens. Interestingly, however, androgen levels are associated with better lung function and these steroid hormones are known to relax smooth muscle in the airways and reduce inflammation, offering potential benefits in the context of asthma.
Here, Dr. Sharifi and his collaborators—including first author Joe Zein, MD, a practicing pulmonologist in the Respiratory Institute—retrospectively analyzed the association between patient genomes and pulmonary function among more than 500 asthmatic patients who received daily oral GC treatment or no GC treatment.
They found that a change to the gene HSD3B1—specifically the HSD3B1(1245A) variant—is associated with poor lung function and GC treatment resistance. Their analysis revealed that among patients receiving GC treatment, those with the HSD3B1(1245A) variant had poorer lung function than those who did not have the genetic variant, suggesting that this genetic change contributes to resistance and helps drive the progression to severe asthma.
It is widely accepted that HSD3B1 encodes an enzyme that converts less active androgens into more potent androgens. While additional research will be necessary, the team suspects that HSD3B1(1245A)’s observed effect on lung function may be attributed to inhibition of this process.
Importantly, this study is the first to provide genetic evidence that suggests variants related to androgen synthesis affect GC treatment resistance in asthma or any other inflammation-related disease.
Dr. Sharifi’s laboratory has extensively studied the role of HSD3B1 in prostate cancer, however. In 2013, he made the seminal discovery that prostate cancer cells with the HSD3B1(1245C) variant survive androgen deprivation therapy, the first line of defense against prostate cancer, by producing their own disease-fueling androgens. He has spent more than seven years studying the variant’s effect in prostate cancer, publishing related findings in Cell, Lancet Oncology, JAMA Oncology and Journal of Clinical Investigation.
Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and directs the Cleveland Clinic Genitourinary Malignancies Research Center. He has joint appointments in the Glickman Urological & Kidney Institute and Taussig Cancer Institute. In 2017, he received the national Top Ten Clinical Achievement Award from the Clinical Research Forum for his discoveries linking HSD3B1(1245C) with poor prostate cancer outcomes.
Dr. Zein is a member of the Cleveland Clinic Asthma Center, which provides a comprehensive approach to asthma management and care along with innovative research, offering patients access to the most advanced diagnostic testing and innovative treatments, including for those living with severe asthma.
This study was supported by the National Heart, Lung, and Blood Institute and the National Cancer Institute, both of the National Institutes of Health.