The associations of human genetic variations with airway microbiome, environmental exposures, and respiratory health

ABSTRACT The intricate interactions between environmental exposures, the respiratory microbiome, and host genetic variations remain inadequately understood in the context of respiratory health. This study utilized sputum metagenomic data from 1,651 individuals in our previous cohort to elucidate these associations. Mendelian randomization indicated that air pollutants (e.g., SO2, CO, and PM2.5) were associated with lung function, which is potentially mediated by microbes, such as Actinomyces, Haemophilus influenzae, and Veillonella spp. Several genetic loci associated with respiratory microbiome variation were found to be linked to genotype-dependent associations between environmental exposures and lung function. For bacteria, the MEOX1 locus (rs1973191819) was associated with lower Filifactor alocis abundance under air pollutant exposure. The FAM110D (1:26157175) and USP36 (rs1343834070) loci showed associations with higher levels of certain pathogenic taxa (e.g., Ralstonia pickettii, Neisseria) and lower levels of the commensal Oribacterium, increasing chronic obstructive pulmonary disease (COPD) risk. For fungi, DNAJC18 and CCDC57 loci exhibited associations with Candida and Penicillium abundance, respectively. These genotype-dependent associations between the microbiome and environmental exposures provide insights into airway dysbiosis and susceptibility to respiratory diseases.IMPORTANCEThis study reveals why individuals exposed to identical air pollution exhibit varying degrees of respiratory severity, pointing to a critical missing link: our genetics. While pollution is a known disease trigger, our findings demonstrate that host genetic variation actively regulates and shapes the respiratory microbiome under environmental stress. By mapping specific genetic loci to pollutant-driven bacterial shifts, this work elucidates how host genetics filters environmental risks to govern microbial homeostasis. These results underscore the necessity of incorporating host-microbiome genetic regulation into environmental health research. Ultimately, this study shifts the paradigm toward personalized medicine, enabling the early identification of at-risk individuals and the development of targeted, microbiome-informed interventions.