Diminished pulmonary function in COPD partly due to genetic risk, smoking interactions

January 07, 2022

2 min read

Disclosures: Kim reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

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Decreased pulmonary function characteristic of COPD may be attributable, in part, to the interaction between genome-wide polygenic risk scores and smoking exposures, according to new research published in JAMA Network Open.

“Only a minority of smokers develop COPD, and genetic factors are thought to account for some of this variation in susceptibility, with approximately 40% of the variability in spirometric measures of pulmonary function attributed to genetic variation,” Woori Kim, PhD, research fellow in the Systems Biology and Computer Science Program at the Ann Romney Center for Neurological Diseases and the department of neurology at Brigham and Women’s Hospital, and colleagues wrote. “Therefore, it has long been thought that airflow obstruction may develop partially as the result of gene-by-smoking interactions.”

Girl smoking a cigarette
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Kim and colleagues analyzed data from the UK Biobank cohort study on 319,730 individuals aged 40 to 69 years (mean age, 56.5 years; 44.4% men) with genetic and spirometry data from 2006 to 2010. These data were analyzed from July 2020 to March 2021. Researchers examined smoking pack-years, ever- vs. never-smoking status and current smoker vs. former- and never-smoking status, in addition to polygenic risk scores of FEV1/FVC ratio.

The primary outcome was FEV1/FVC ratio.

Overall, 24,915 (8%) individuals had moderate to severe COPD.

The researchers reported polygenic risk score (beta = – .03) and smoking pack-years (beta = – .0064) were significantly associated with lower FEV1/FVC and the interaction term (beta = – .0028).

The researchers also reported a stepwise increment in estimated effect sizes for interaction terms per 10 pack-years of smoking exposure. There was an interaction of polygenic risk score with 11 to 20 pack-years of smoking (beta = – .0038), 31 to 30 pack-years (beta = – .013) and more than 50 pack-years (beta = – .017). In addition, researchers observed evidence of an interaction between polygenic risk score and ever- or never-smoking status (beta = – .0064) and current or noncurrent smoking status (beta = – .0091).

FEV1/FVC was significantly lower among individuals at highest genetic risk compared with individuals at lowest risk. For every 20 pack-years of smoking, individuals at the highest genetic risk had an almost a twofold reduction in FEV1/FVC compared with individuals at lowest risk (beta = – .0084 vs. beta = – .017), according to the results.

According to the researchers, large-scale replication and further investigation into mechanisms of interaction are required.

“These findings suggest that elucidating mechanisms for the interaction between smoking and genetic risk could yield greater insight into the chronic obstructive pulmonary disease pathogenesis,” the researchers wrote.

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