Chronic periodontitis and respiratory diseases: A bidirectional two-sample Mendelian randomization study

Evidence from observational research suggests potential links between chronic periodontitis (CP) and respiratory diseases, but these associations remain susceptible to residual confounding and reverse causation. This study aimed to evaluate whether CP exerts a direct causal influence on chronic obstructive pulmonary disease, asthma, or pneumonia and whether these respiratory diseases in turn affect the risk of periodontitis. Using a bidirectional two-sample Mendelian randomization design, we extracted summary-level genome-wide association study data from large publicly available cohorts and applied inverse-variance weighting as the primary analytical approach, complemented by Mendelian randomization-Egger, weighted median, simple mode, and weighted mode estimators. Horizontal pleiotropy, outliers, and heterogeneity were examined through Mendelian randomization-Pleiotropy RESidual Sum and Outlier, heterogeneity statistics, and leave-one-out analyses. Across all primary analyses and robustness checks, the results consistently indicated no evidence for a direct causal relationship between CP and any of the respiratory diseases examined in either direction. Findings were stable across sensitivity analyses and replication using alternative datasets. While these results do not support a causal interpretation of previously reported epidemiological associations, the observed null effects should be interpreted with consideration of instrument limitations, phenotype heterogeneity, and ancestry constraints. Further research incorporating refined disease subtypes, multivariable Mendelian randomization, functional genomic integration, and diverse populations is warranted to clarify the biological pathways linking oral and respiratory health.