PDGFD Gene Mutation Linked to Increased Risk of Corticosteroid-Induced Adrenal Suppression

Alice Melão, MSc avatar

by Alice Melão, MSc |

Share this article:

Share article via email
PDGFD adrenal suppression

A mutation of the PDGFD gene is linked to an increased risk of adrenal gland suppression, a serious side effect of inhaled corticosteroids used to treat asthma and chronic obstructive pulmonary disease (COPD), researchers have found.

The discovery, reported in the study, “Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study using data from PASS and PASIC,” can help identify patients at risk for this condition, and improve the safety and effectiveness of corticosteroid treatment. It was published in the journal Lancet Respiratory Medicine.

Adrenal suppression impairs the production of cortisol, an important hormone that regulates the body’s response to stress, as well as blood pressure and metabolism.

The incidence of corticosteroid-induced adrenal suppression varies greatly, depending on administration route and time of treatment. The condition can be difficult to diagnose because it has been linked to a wide range of symptoms, ranging from nonspecific symptoms, such as tiredness, to serious illnesses and even death. It is still unclear why some patients are more affected than others, or why some don’t develop the condition at all while using similar doses of corticosteroids.

In an attempt to find a genetic factor that could help explain this variability, a team led by researchers at the University of Liverpool conducted a genome-wide association study (GWAS).

The study included data from 499 children with asthma, from 25 sites across the U.K., who participated in the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. Among these patients, 35 percent had reduced levels of cortisol (less than 500 nmol/L), suggestive of adrenal suppression.

Genetic analysis revealed 20 genetic mutations affecting the PDGFD gene that were significantly associated with corticosteroid-induced low cortisol levels in these children.

Researchers decided to further investigate this association in two new groups of patients, 78 adult patients with COPD and 81 children with asthma. In this new analysis, the team focused on one specific genetic mutation of PDGFD, identified as rs591118, which they had found increased the risk of having peak cortisol levels of less than 350 nmol/L by 7.32 times.

The validation analysis confirmed that the rs591118 mutation was associated with a higher risk of adrenal suppression by more than two times in both adult and pediatric patients. The risk was even higher if the patients had two copies of the gene muatation (one inherited from the mother and other from the father).

“This is the first pharmacogenomic study investigating the association between a patient’s genotype [genetic sequence] and corticosteroid induced adrenal suppression,” Daniel Hawcutt, MD, senior lecturer of the pediatric clinical pharmacology at the University of Liverpool and lead author of the study, said in a university press release. “Our highly novel findings offer the potential to develop personalized approaches therapy.”

Hawcutt believes that based on each patient’s PDGFD genetic profile, it may be possible to identify patients at risk and design a treatment strategy to avoid or minimize steroid use while monitoring their adrenal function.

“However, it is important to stress that steroids are effective medications, and patients should not stop taking these medicines without medical input,” he said.

Each case should be evaluated individually and carefully managed by the patient’s clinical and care team, the researcher suggested.