Smoking Interaction with a Polygenic Risk Score for Reduced Lung Function
Authors: Kim Woori , Moll Matthew , Qiao Dandi , Hobbs Brian D. , Shrine Nick , Sakornsakolpat Phuwanat , Tobin Martin D. , Dudbridge Frank , Wain Louise V. , Ladd-Acosta Christine , Chatterjee Nilanjan , Silverman Edwin K. , Cho Michael H. , Beaty Terri H. 
Published: March 2021

Importance

Risk to airflow limitation and Chronic Obstructive Pulmonary Disease (COPD) is influenced by combinations of cigarette smoking and genetic susceptibility, yet it remains unclear whether gene-by-smoking interactions contribute to quantitative measures of lung function.

Objective

Determine whether smoking modifies the effect of a polygenic risk score’s (PRS’s) association with reduced lung function.

Design

United Kingdom (UK) Biobank prospective cohort study.

Setting

Population cohort.

Participants

UK citizens of European ancestry aged 40-69 years, with genetic and spirometry data passing quality control metrics.

Exposures

PRS, self-reported pack-years of smoking, ever-versus never-smoking status, and current-versus former-/never-smoking status.

Main Outcomes and Measures

Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC). We tested for interactions with models including the main effects of PRS, different smoking variables, and their cross-product term(s). We also compared the effects of pack-years of smoking on FEV1/FVC for those in the highest versus lowest decile of predicted genetic risk for low lung function.

Results

We included 319,730 individuals (24,915 with moderate-to-severe COPD). The PRS and pack-years were significantly associated with lower FEV1/FVC, as was the interaction term (β [interaction] = −0.0028 [95% CI: −0.0029, −0.0026]; all p < 0.0001). A stepwise increment in estimated effect sizes for these interaction terms was observed per 10 pack-years of smoking exposure (all p < 0.0001). There was evidence of significant interaction between PRS with ever/never smoking status (β [interaction] = −0.0064 [95% CI: −0.0068, −0.0060]) and current/not-current smoking (β [interaction] = −0.0091 [95% CI: −0.0097, −0.0084]). For any given level of pack-years of smoking exposure, FEV1/FVC was significantly lower for individuals in the tenth compared to the first decile of genetic risk (p < 0.0001). For every 20 pack-years of smoking, those in the top compared to the bottom decile of genetic risk showed nearly a twofold reduction in FEV1/FVC.

Conclusions and Relevance

COPD is characterized by diminished lung function, and our analyses suggest there is substantial interaction between genome-wide PRS and smoking exposures. While smoking has negative effects on lung function across all genetic risk categories, effects of smoking are highest in those with higher predicted genetic risk.

Key Points

Question

Does cigarette smoking modify the magnitude of genetic effects on forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC)?

Findings

FEV1/FVC is influenced by PRS-by-smoking interactions. Smoking was detrimental across all categories of predicted genetic risk, though it was worse for those with highest predicted genetic risks. For every reported 20 pack-years of reported smoking, individuals in the top compared to the bottom decile of genetic risk showed nearly twice the reduction in FEV1/FVC.

Meaning

Elucidating mechanisms for the interaction between smoking and genetic risk could yield greater insight into the pathogenesis of chronic obstructive pulmonary disease (COPD).