Abstract Rationale Alpha-1 antitrypsin (AAT) deficiency, primarily caused by homozygous SERPINA1 Z mutation, increases the risk of COPD. Individuals carrying one Z and one normal M allele (MZ) have higher COPD risk than MM individuals, although many never develop disease. COPD is a polygenic condition influenced by numerous genetic factors across the genome and by environmental exposures such as smoking. We aimed to examine how polygenic factors and smoking modify risk of airflow obstruction in MZ compared with MM. Methods We included participants with the MZ and MM genotypes from the Framingham Heart Study. We first tested the association between AAT genotype (MZ coded as 1 and MM as 0) and FEV1/FVC, stratified by ever-smoking status, and further evaluated interactions between AAT genotype and smoking pack-years. Next, for each participant we calculated a polygenic risk score (PRS) for FEV1/FVC, which was derived from external genome-wide association studies in the UK Biobank and SpiroMeta Consortium. To reflect risk for airflow limitation, higher PRSs correspond to lower FEV1/FVC. We then tested the interaction between the PRS and AAT genotype, stratified by ever-smoking. Models were adjusted for age, sex, height, current smoking, pack-years (among ever-smokers), familial relatedness, and in PRS models, principal components of genetic ancestry. Results Among 4,220 participants (mean age 53.7 years, 54.2% female, 50.2% ever-smokers, mean FEV1/FVC 74.6%), 133 (3.2%) had MZ genotype. In never-smokers, MZ individuals had 1.72% higher FEV1/FVC compared with MM (P = 0.032), whereas no difference was observed among ever-smokers (β= -0.39%; P = 0.65). Cumulative smoking modified the effect of MZ genotype on FEV1/FVC (interaction β= -0.13% per pack-year; P = 0.003); this interaction persisted among ever-smokers (β= -0.11% per pack-year; P = 0.044). A one-standard-deviation increase in the FEV1/FVC PRS was associated with lower FEV1/FVC in both never- (β= -2.37%; P 0.0001) and ever-smokers (β= -2.46%; P 0.0001). A higher PRS was disproportionately associated with reduced FEV1/FVC in MZ compared to MM (interaction β= -1.87% per standard-deviation PRS increase, P = 0.027) among ever-smokers, but not in never-smokers (P = 0.15). Conclusions In this community-based cohort, the AAT MZ genotype was associated with higher FEV1/FVC among non-smokers compared to MM. The interaction between MZ genotype and pack-years suggested a dose-dependent modifying effect of smoking on the MZ-related COPD risk. Among ever-smokers, higher polygenic risk further amplified susceptibility to airflow obstruction in MZ compared with MM. These findings highlight the roles of both polygenic and environmental risk factors in COPD susceptibility in MZ. Replication of the results is needed. This abstract is funded by: This work is supported by an Alpha-1 Foundation Grant and a Boston University Department of Medicine Career Investment Award
Zhang et al. (Fri,) studied this question.