'Big data' analysis reveals that androgens could benefit asthma

A group of researchers based at Indiana University School of Medicine and Riley Hospital for Children at IU Health has discovered that people who are clinically lacking androgen effects are three to four times more likely to have asthma than people in the general population.  Their “big data” analysis of over 90 million people supports previous work in mice showing that loss of the androgen receptor increases asthma risk. Led by Benjamin Gaston, MD, “Asthma risk among individuals with androgen receptor deficiency,” was published in JAMA Pediatrics.

People of all genders produce androgens, a type of hormone that communicates with different cells in the body through a protein called the androgen receptor.  The risk of asthma in people with androgen insensitivity syndrome (AIS), who typically have androgen receptor deficiency, has not been previously studied. Gaston said that the question came up while his team was conducting research related to SARS-CoV-2, the virus that causes COVID-19.

“Because of studying COVID-19, we discovered that human airways express androgen receptors, and that increased AR expression, while bad if you have COVID, is good if you have asthma,” said Gaston, who is the Billie Lou Wood Professor of Pediatrics and the Department of Pediatrics Vice Chair of Translational Research at Riley Hospital and IU School of Medicine.

Gaston and his team partnered with scientists at Cleveland Clinic and Vanderbilt University to gather and analyze electronic medical record (EMR) data for 90 million people from IBM Explorys and the Regenstrief Institute. These databases are “de-identified,” meaning the investigators can compare numeric diagnosis codes without knowing the identity of individual patients. This allows large scale, useful analyses of information without risk to patient confidentiality. It was this analysis that uncovered higher rates of asthma in people with partial or complete androgen insensitivity syndrome (AIS).  

Interestingly, Gaston said, this discovery and its approach complements another recent publication from his team. In it, the investigators studied all of the thousands of messenger RNA molecules, reflecting gene expression, in the airway-lining cells of specific, well-characterized patients with asthma.  This computer-based analysis of RNA sequencing (“RNASeq”) data permits analysis of which genes are turned on or off in a given individual.  Androgen receptor genes were turned on in individuals with the best-controlled asthma.  This work was a collaboration between Gaston’s group and the multi-site Severe Asthma Research Program.  The study, titled “Benefits of androgen receptor expression in human asthma,” has just been published in the American Journal of Respiratory and Critical Care Medicine.

Gaston said that the findings from these two, complementary studies suggest that androgens could benefit specific patients with asthma. Now, he and his team at Riley are planning mechanistic studies to understand the relationship between androgens and asthma. They’re also planning clinical studies for patients who have both severe asthma and low androgen levels and are looking into whether or not androgen receptor deficiency is associated with higher risk for other obstructive lung diseases.

Additional scientists contributing to this work include Nadzeya Marozkina, MD, PhD, of IU School of Medicine; Dawn C. Newcomb, PhD, of Vanderbilt University Medical Center; Nima Sharifi, MD, and Joe Zein, MD, PhD of the Cleveland Clinic Lerner Research Institute.  This groundbreaking work was supported by the National Institutes of Health, along with the Riley Children’s Foundation.

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