Smoking Interaction with a Polygenic Risk Score for Reduced Lung Function

Abstract

ImportanceRisk 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. ObjectiveDetermine whether smoking modifies the effect of a polygenic risk scores (PRSs) association with reduced lung function. DesignUnited Kingdom (UK) Biobank prospective cohort study. SettingPopulation cohort. ParticipantsUK citizens of European ancestry aged 40-69 years, with genetic and spirometry data passing quality control metrics. ExposuresPRS, self-reported pack-years of smoking, ever-versus never-smoking status, and current-versus former-/never-smoking status. Main Outcomes and MeasuresForced 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. ResultsWe 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 ({beta} [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 ({beta} [interaction] = -0.0064 [95% CI: -0.0068, -0.0060]) and current/not-current smoking ({beta} [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 RelevanceCOPD 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 PointsO_ST_ABSQuestionC_ST_ABSDoes cigarette smoking modify the magnitude of genetic effects on forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC)? FindingsFEV1/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. MeaningElucidating mechanisms for the interaction between smoking and genetic risk could yield greater insight into the pathogenesis of chronic obstructive pulmonary disease (COPD).