A common genetic variation in the SERPINE1 gene influences how children with asthma respond to viral infections and biologic therapies like mepolizumab, potentially enabling personalized treatment decisions based on genetic markers.
- The SERPINE1 gene produces a protein linked to severe asthma exacerbations, with the risk-associated 4G variant found in approximately 60% of studied populations.
- Children carrying the 4G variant show lower SERPINE1 activity normally but dramatically higher expression during viral infections, leading to increased inflammation and immune activation.
- The 4G variant is associated with a 2.6-fold increased risk of severe asthma attacks and may explain why some patients don't respond adequately to mepolizumab therapy.
A common genetic variation found in millions of children with asthma may explain why some patients respond differently to viral infections and biologic treatments. That’s according to the paper, “SERPINE1 Promoter Variants and Differential Airway Responses to Virus and Biological Therapy,” recently published in The Journal of Allergy and Clinical Immunology.
Researchers investigating the SERPINE1 gene found that variations within it significantly alter airway responses, accounting for differences in how children respond to the asthma biologic drug mepolizumab.
The SERPINE1 gene produces plasminogen activator inhibitor-1 (PAI-1), a protein previously linked to severe asthma exacerbations. Investigators analyzed nasal airway samples from children aged six to 17 years of age participating in the MUPPITS-1 and MUPPITS-2 asthma research cohorts. Both trials included children with exacerbation-prone asthma living in urban environments. SERPINE1 is designated as a 4G variant because of promoter region variant where either four or five (5G) guanine (G) bases are present in a repetitive sequence.
Researchers discovered that children carrying the risk-associated 4G variant exhibited lower levels of SERPINE1 activity under normal conditions but showed substantially higher gene expression during viral illnesses. These children also demonstrated increased activation of immune signaling pathways and other inflammatory networks linked to asthma exacerbations, they said.
According to researchers, the findings may explain why SERPINE1 has been associated with a 2.6-fold increased risk of severe asthma attacks, despite being present in approximately 60% of individuals studied across multiple populations.
Investigators observed that viral infections triggered heightened activity in pathways involving immune responses, Toll-like receptor signaling and tissue remodeling, although some antiviral response pathways appeared diminished among children carrying the risk allele.
The study also explored how the genetic variant interacts with mepolizumab, an anti-IL-5 biologic therapy commonly prescribed for severe eosinophilic asthma. Researchers identified several significant gene-by-drug interactions, suggesting that a patient’s genetic makeup may influence treatment outcomes.
Among children carrying the risk variant who received mepolizumab and still experienced asthma exacerbations, investigators observed increased activity in pathways associated with TGF-β/SMAD3 signaling and epithelial remodeling. These biological processes have previously been linked to airway damage and worsening asthma symptoms, they noted.
Researchers said they believe the findings suggest that some inflammatory and epithelial pathways may remain active despite successful suppression of IL-5-driven eosinophilic inflammation by mepolizumab. Additionally, they believe genetic markers such as SERPINE1 variants could eventually help physicians personalize biologic treatment decisions and identify patients who may require additional therapeutic approaches.
The study’s authors said further prospective studies are needed to confirm whether SERPINE1 variants directly influence clinical responses to mepolizumab and other biologic therapies targeting type 2 inflammation. They also suggested future research into treatments aimed at PAI-1-associated pathways, which could provide new options for patients who continue to experience exacerbations despite current therapies.
