Bronchodilator Response Outperforms Genetic Risk in Predicting COPD Progression

A recent study found that bronchodilator responsiveness was more strongly associated with progression to chronic obstructive pulmonary disease (COPD) and decline in forced expiratory volume in 1 second (FEV₁) than polygenic risk scores.1

“In conclusion… [bronchodilator responsiveness] enhances the predictive ability of clinical models for COPD progression in [non-Hispanic White participants], whereas adding [polygenic risk scores] did not,” wrote study investigator Spyridon Fortis, MD, from the division of pulmonary, critical care, and occupational medicine at the University of Iowa Hospital and Clinics, and colleagues.

Bronchodilator responsiveness has been associated with lung function decline and progression to chronic obstructive pulmonary disease (COPD), although evidence is mixed regarding its ability to predict COPD development.2 Polygenic risk scores (PRS) are known to predict reduced lung function and increased COPD risk.

Investigators aimed to determine whether genetic predisposition to COPD is associated with bronchodilator responsiveness and whether these factors independently or jointly influence lung function decline among individuals at risk for COPD.1

To address these questions, the investigators conducted a cross-sectional analysis using data from 4,824 adults aged 45–80 years enrolled in the US-based, multicenter COPDGene study. All participants had a ≥10 pack-year smoking history and normal spirometry at baseline. The cohort included 1,446 African American and 3,378 non-Hispanic White participants.1

Genetic risk was evaluated in relation to bronchodilator responsiveness, defined as the percent increase in forced expiratory volume in 1 second (FEV₁) following bronchodilator administration. Responsiveness was assessed using pre-bronchodilator lung function measured in 2005 and predicted lung function in 2021 as reference points.1

The study revealed that genetic risk was not correlated with bronchodilator response in African American individuals (P =.82) but had a slight, albeit weak, correlation in non-Hispanic White individuals (P <.001). Non-Hispanic White participants with bronchodilator responsiveness exhibited a greater polygenic risk score than those without.1

The team noted that prediction models that included bronchodilator responsiveness measured in 2005 were more accurate than models that included polygenic risk scores. This was true in both non-Hispanic White and African American participants, as shown by greater area under the curve (AUC) values in each group (AUC, 0.762 vs 0.743 for White participants (P =.0004); 0.693 vs 0.653 for African Americans).1

Additionally, among White participants, people whose lungs responded more strongly to a bronchodilator tended to experience faster declines in lung function over time. For example, a 10% greater bronchodilator response in 2005 was linked to losing 14.8 mL of lung volume per year, and a 10% higher response in 2021 was linked to losing about 18.3 mL per year. By comparison, a higher genetic risk score was associated with a much smaller decline of about 2.7 mL per year.1

Models that included bronchodilator response explained the changes in lung function better than those using genetics alone. There was also some evidence that genetics and bronchodilator response together affected lung decline, but this was only seen for the 2005 measurements.1

In mediation analyses, differences in bronchodilator responsiveness explained roughly one-third of the association between polygenic risk and long-term FEV₁ decline. However, no significant mediation was observed for acute bronchodilator-related changes in FEV₁, consistent with the lack of association between polygenic risk and bronchodilator responsiveness.1

“…our findings suggest that while PRS and BDR may share biological pathways influencing FEV1 decline, they also capture distinct dimensions of COPD susceptibility—PRS reflecting inherited risk for impaired lung development and decline, and BDR reflecting airway responsiveness and inflammation,” investigators wrote. “These findings highlight that [bronchodilator responsiveness] captures airway disease processes beyond genetic susceptibility and remains a more robust predictor of COPD progression across populations.”

References

1. Fortis S, Comellas AP, Bowler RP, et al. Relationships between bronchodilator responsiveness, a COPD polygenic risk score, and COPD progression. Respir Med. Published online January 9, 2026. doi:10.1016/j.rmed.2026.108636

2. Halpin DMG. Bronchodilator Responsiveness in Asthma and Chronic Obstructive Pulmonary Disease: Time to Stop Chasing Shadows. Am J Respir Crit Care Med. 2024;209(4):349-351. doi:10.1164/rccm.202312-2248ED