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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., SO\n                      <jats:sub>2<\/jats:sub>\n                      , CO, and PM\n                      <jats:sub>2.5<\/jats:sub>\n                      ) were associated with lung function, which is potentially mediated by microbes, such as\n                      <jats:italic toggle=\"yes\">Actinomyces<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Haemophilus influenzae<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Veillonella<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">MEOX1<\/jats:italic>\n                      locus (rs1973191819) was associated with lower\n                      <jats:italic toggle=\"yes\">Filifactor alocis<\/jats:italic>\n                      abundance under air pollutant exposure. The\n                      <jats:italic toggle=\"yes\">FAM110D<\/jats:italic>\n                      (1:26157175) and\n                      <jats:italic toggle=\"yes\">USP36<\/jats:italic>\n                      (rs1343834070) loci showed associations with higher levels of certain pathogenic taxa (e.g.,\n                      <jats:italic toggle=\"yes\">Ralstonia pickettii<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Neisseria<\/jats:italic>\n                      ) and lower levels of the commensal\n                      <jats:italic toggle=\"yes\">Oribacterium<\/jats:italic>\n                      , increasing chronic obstructive pulmonary disease (COPD) risk. For fungi,\n                      <jats:italic toggle=\"yes\">DNAJC18<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">CCDC57<\/jats:italic>\n                      loci exhibited associations with\n                      <jats:italic toggle=\"yes\">Candida<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Penicillium<\/jats:italic>\n                      abundance, respectively. These genotype-dependent associations between the microbiome and environmental exposures provide insights into airway dysbiosis and susceptibility to respiratory diseases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>This 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.00442-26","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:00:46Z","timestamp":1785330046000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["The associations of human genetic variations with airway microbiome, environmental exposures, and respiratory health"],"prefix":"10.1128","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7674-1943","authenticated-orcid":false,"given":"Shifen","family":"Xu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01kq0pv72","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangdong Engineering Research Center of Precision Detection and 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