Mutation Present in Genome of Some Asthma Patients Is Responsible for Resistance to Glucocorticoid Treatment

A genetic variant has been identified that causes depressed lung function among asthma patients and reduces their response to glucocorticoid treatment.

Asthma is a chronic lung disease that inflames and narrows the airways. Asthma causes recurring periods of wheezing, chest tightness, shortness of breath, and coughing. The coughing often occurs at night or early in the morning. Asthma affects people of all ages, but it most often starts during childhood. Childhood-onset and adult-onset asthma differ with respect to severity and associated syndromes.

Higher doses of oral or inhaled glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment for asthma. Glucocorticoids are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as inflammation. They are therefore used to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. Glucocorticoids affect cells by binding to the glucocorticoid receptor. The activated glucocorticoid receptor-glucocorticoid complex up-regulates the expression of anti-inflammatory proteins in the nucleus and represses the expression of pro-inflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus.

Although resistance to glucocorticoids is a major clinical problem, the underlying mechanisms are unknown. In population studies, animal models, and cell culture experiments, androgens were associated with several benefits in asthma, but neither androgen use in glucocorticoid-resistant asthma nor the genetic determinants of androgen responsiveness have been studied in humans. In this regard, investigators at the Cleveland Clinic (OH, USA) analyzed the association between genomes and lung function in more than 500 asthmatic patients who received daily oral glucocorticoids treatment or no glucocorticoids treatment at all.

Results revealed that a mutation in the HSD3B1 gene - specifically the HSD3B1(1245A) variant - was associated with poor lung function and glucocorticoid treatment resistance. The HSD3B1 gene encodes the enzyme 3-beta-hydroxysteroid dehydrogenase-1 (3-beta-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to more potent androgens. It is possible that the effect of the HSD3B1(1245A) variant on lung function may be attributed to inhibition of this process.

“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,” said senior author Dr. Nima Sharifi, director of the genitourinary malignancies research center at the Cleveland Clinic. “These findings make the case for genetic testing and personalized treatment and provide important information for identifying which patients should be treated using different therapies.”

The study was published in the January 13, 2020, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences.

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