Abstract Background Chronic Obstructive Pulmonary Disease (COPD) associated with Alpha-1 Antitrypsin Deficiency (AATD) exhibits sex differences in onset and progression, with males experiencing higher COPD risk and more rapid lung function decline. Sex hormones modulate immune responses, but the roles of sex hormones and inflammatory proteins in sex-specific COPD heterogeneity remain unclear. We hypothesized that distinct profiles of sex hormones and inflammatory mediators in males and females contribute to COPD differences in AATD, and aimed to identify sex-specific predictors of lung function by integrating systemic inflammatory protein and sex hormone profiling. Methods We analyzed 398 adults (221 females, 177 males) with severe AATD (PiZZ genotype) from the Alpha-1 Antitrypsin Genetic Modifiers Study. Plasma inflammatory proteins were measured via the Olink Explore 384 Inflammation panel. Serum sex hormone levels (SHBG, total/free testosterone, dihydrotestosterone, estradiol, estrone) were measured in a subset of 145 participants. Linear regression assessed associations between protein/hormone levels and COPD status, FEV1, and FEV1/FVC, adjusting for age and smoking history, using sex-stratified and sex-interaction models. Interactions between sex hormones and proteins in predicting lung function were also tested. Results Proteomic analysis revealed sex-specific inflammatory signatures that were associated with lung function among individuals with AATD. In females, eight proteins were significantly associated with FEV1/FVC ratio (FDR 0.05), while in males, seventeen proteins were identified, with only one shared protein marker (AGER) across both sexes, highlighting divergent molecular markers of lung function by sex. To assess the impact of circulating sex hormones, we tested for the interaction between sex hormones and proteins on lung function at FDR0.05. In females, higher estradiol levels were positively associated with ITM2A abundance, and their interaction predicted better lung function, suggesting a potential protective and modulatory role for estradiol in females with AATD. Conversely, in males, elevated testosterone levels were negatively associated with the inflammatory proteins ENPP5, OMD, and MEPE, and the interactions between testosterone and these markers predicted reduced lung function. Conclusion Our study identified sex-specific inflammatory proteins that are associated with lung function in AATD-associated COPD, with some of these associations influenced by sex hormones. Estradiol appears protective in females, while higher testosterone in males is linked to reduced lung function through its interaction with key inflammatory proteins. These findings highlight the role of sex hormones and systemic inflammatory markers in lung function, underscoring the need for sex- and hormone-informed approaches in the management and therapeutic targeting of AATD-associated COPD. This abstract is funded by: Alpha-1 Foundation
Lopes-Ramos et al. (2026) studied this question.