Newly Discovered Genetic Variant Could Help Predict Common Asthma Therapy Side Effect

Sir Munir Pirmohamed, PhD

In the first study of its kind, new research has linked inhaled corticosteroids (ICS) to adrenal suppression in asthma and chronic obstructive pulmonary disease (COPD) patients who have a genetic variant in the platelet-derived growth factor D (PDGFD) gene.

“Not only did we identify a completely novel locus in PDGFD, but we were able to validate this in another pediatric asthma cohort and then in an adult COPD cohort,” lead author Sir Munir Pirmohamed, PhD, of the University of Liverpool, told MD Magazine.

Generally, ICS are well tolerated and have less side effects than oral corticosteroids. But some asthma and COPD patients experience harmful effects, such as adrenal suppression. This can be dangerous, especially for children with asthma since their symptoms can range widely from asymptomatic, to acute adrenal crisis, where cortisol levels are insufficient.

Researchers recruited subjects into the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study and the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. They were divided into 3 cohorts: 499 children in the discovery cohort, 81 children in the pediatric validation cohort, and 78 adults in the adult COPD validation cohort.

Adrenal suppression was tested by conducting the low-dose short synacthen test and defined as a peak cortisol level of less than 500 nmol/L in adults and less than 350 nmol/L in children. DNA samples were taken from all three cohorts for the genotype analysis.

In the pediatric discovery cohort, 40 single nucleotide polymorphisms (SNPs) were associated with adrenal suppression, including an intronic SNP within the PDGFD gene locus (rs591118 [OR 7.32; 95% CI; 3.15 - 16.99; P = 5.8x10-8]). This finding for the gene locus was corroborated in both the pediatric validation cohort (OR 3.86; 95% CI; 1.19 - 12.50; P = 0.02) and adult COPD cohort (OR 2.41; 1.10 - 5.28; P = 0.03).

Adrenal suppression by the genotype were in 3% of the 214 patients with the GG genotype, 6% of the 244 with the AG genotype, and 25% of the 87 with the AA genotype. Meta-analysis of the pediatric cohorts and the adult COPD cohorts showed genome-wide significance of rs591118 (OR 5.89; 95% CI; 2.97 - 11.68; P = 4.3x10-9; and OR 4.05; 2.00 - 8.21; P = 3.5x10-10, respectively).

“The results from the COPD adult cohort are particularly interesting given that COPD is a different disease, the patients were much older than in the asthma cohort, were on multiple drugs, and had multiple co-morbidities,” Pirmohamed said.

These results are significant because if medical professionals can identify patients susceptible to adrenal suppression from ICS, they can be monitored closely by taking the low-dose synacthen testing or avoid steroids if other viable treatments are available.

However, while this study tested the largest cohort of children with asthma for adrenal suppression, Pirmohamed said the total number of patients with adrenal suppression was still low.

“This is a possible limitation, despite the fact that we validated in other cohorts,” Pirmohamed said. “It would be good to see replication in different cohorts, to understand the mechanism behind this genetic association, and design clinical studies to assess the clinical utility of this genetic predisposing factor.”

The study, "Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study," was published online in The Lancet Respiratory Medicine last week.