A recent study reveals that a higher genetic risk for chronic obstructive pulmonary disease (COPD) may be associated with reduced lung function beginning as early as childhood and continuing into adulthood—regardless of smoking status.
The study, published in EClinicalMedicine, assessed 45,406 participants aged 4 to 50 years across 16 cohorts. Researchers observed an association between a higher polygenic risk score (PRS) for COPD and reduced lung function from childhood through adulthood. This investigation, conducted within the Chronic Airway Diseases Early Stratification (CADSET) Clinical Research Collaboration, utilized a PRS derived from 82 genetic variants identified in a large genome-wide association study focused on airflow limitation—a hallmark of COPD.
The study identified notable associations between the PRS and reduced prebronchodilator forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FEV1/FVC) ratios, beginning in children aged 7 to 10 years (β: −0.13 z-scores per one PRS z-score increase [−0.15, −0.11], q-value = 7.04 × 10−53) and continuing into adulthood, specifically ages 41 to 50 years (β: −0.16 [−0.19, −0.13], q-value = 1.31 × 10−24).
Similarly, a meaningful link was found between the PRS and decreased FEV1, starting from school age (7-10 years; β: −0.07 [−0.09, −0.05], q-value = 1.65 × 10−9) and continuing into adulthood (41-50 years; β: −0.17 [−0.20, −0.13], q-value = 4.48 × 10−20).
The PRS explained up to 6.5% of the variance in FEV1/FVC ratios across different age groups, highlighting the measurable but modest contribution of genetic factors to lung function decline over time.
Participants in the highest decile of the PRS distribution exhibited notably lower lung function than those in the lowest decile, with a mean FEV1/FVC z-score of −0.62 in adults aged 18 to 30 years in the top decile compared to −0.11 in those in the bottom decile. In individuals older than 50, a comparable effect size was found, with a mean FEV1/FVC z-score of −0.91 in the highest PRS decile compared to −0.26 in the lowest decile (β: −0.64, 95% confidence interval: −0.75, −0.53, p-value = 8.20 × 10−29, q-value = 2.40 × 10−27).
The sensitivity analyses revealed that the association between the PRS and lung function persisted even after adjusting for smoking status, cumulative smoking exposure (pack-years), and asthma, underscoring the genetic influence on lung function independent of these environmental factors. These associations were consistent regardless of smoking status, sex, or asthma diagnosis, reinforcing that genetic predisposition to COPD influences lung function independent of these variables.
To contextualize the impact of the PRS on lung function, the study compared its genetic contribution to that of other complex traits, such as body mass index (2.4%–9.5%) and blood pressure (0.5%–7.5%), illustrating the relative significance of genetic predisposition in lung function decline. These findings suggested a role for genetic factors in COPD pathophysiology from an early age, with potential implications for early identification and intervention.
This study was funded by the European Respiratory Society’s CADSET Clinical Research Collaboration and received additional support from several pharmaceutical companies.
