Year: 2021
Type: article
Study design: Observational Study
Abstract: Importance: The risk of 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 are associated with quantitative measures of lung function. Objective: To assess the interaction of cigarette smoking and polygenic risk score in association with reduced lung function. Design, Setting, and Participants: This UK Biobank cohort study included UK citizens of European ancestry aged 40 to 69 years with genetic and spirometry data passing quality control metrics. Data was analyzed from July 2020 to March 2021. Exposures: PRS of combined forced expiratory volume in 1 second (FEV1) and percent of forced vital capacity exhaled in the first second (FEV1/FVC), self-reported pack-years of smoking, ever- vs never-smoking status, and current- vs former- or never-smoking status. Main Outcomes and Measures: FEV1/FVC was the primary outcome. Models were used to test for interactions with models, including the main effects of PRS, different smoking variables, and their cross-product terms. The association between pack-years of smoking and FEV1/FVC were compared for those in the highest vs lowest decile of estimated genetic risk for low lung function. Results: We included 319 730 individuals, of whom 24 915 (8%) had moderate-to-severe COPD cases, and 44.4% were men. Participants had a mean (SD) age 56.5 of (8.02) years. The PRS and pack-years were significantly associated with lower FEV1/FVC (PRS: β, -0.03; 95% CI, -0.031 to -0.03; pack-years: β, -0.0064; 95% CI, -0.0064 to -0.0063) and the interaction term (β, -0.0028; 95% CI, -0.0029 to -0.0026). A stepwise increment in estimated effect sizes for these interaction terms was observed per 10 pack-years of smoking exposure. The interaction of PRS with 11 to 20, 31 to 40, and more than 50 pack-years categories were β (interaction) -0.0038 (95% CI, -0.0046 to -0.0031); -0.013 (95% CI, -0.014 to -0.012); and -0.017 (95% CI, -0.019 to -0.016), respectively. There was evidence of significant interaction between PRS with ever- or never- smoking status (β, interaction; -0.0064; 95% CI, -0.0068 to -0.0060) and current or not-current smoking (β, interaction; -0.0091; 95% CI, -0.0097 to -0.0084). For any given level of pack-years of smoking exposure, FEV1/FVC was significantly lower for individuals in the tenth decile (ie, highest risk) than the first decile (ie, lowest risk) of genetic risk. For every 20 pack-years of smoking, those in the tenth decile compared with the first decile of genetic risk showed nearly a 2-fold 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 was associated with decreased lung function across all genetic risk categories, the associations were strongest in individuals with higher estimated genetic risk.
Source: JAMA Network Open
Institutions: Broad Institute, Brigham and Women's Hospital, Harvard University, Massachusetts Institute of Technology, University of Leicester, Siriraj Hospital, Mahidol University, Glenfield Hospital, National Institute for Health and Care Research, Johns Hopkins University, National Institutes of Health, Division of Cancer Epidemiology and Genetics
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: G1488503895, Large-scale genomic epidemiology approaches to study the natural history of lung function and COPD, Identifying functional variants in COPD GWAS loci, Genetic and Functional Dissection of a Cluster of COPD GWAS Signals on Chromosome 4q, G3842720522, G3851224574, G485517832, NIHR Senior Investigator Award, G5520316217, (2 of 2) Genetic Epidemiology of COPD, G5850737185, Multi-omic Subtyping of Chronic Obstructive Pulmonary Disease, G5960470374, G7531143628, G7732978665, G8245670873, G8354759825, G9000228787, COPD Susceptibility, Heterogeneity, and Progression: Proteomics and Genetics, Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers, SYSTEMS APPROACHES TO THE EPIDEMIOLOGY, GENETICS AND GENOMICS OF LUNG DISEASES, Genetic and Genomic Characterization of the Occurrence and Progression of Interstitial Lung Abnormalities
OpenAlex ID: W4200002844