Genetic Liability to COPD and Periodontitis Risk: Integrative Genetic and Single-Cell Evidence Implicating Macrophage Reprogramming.
Chronic obstructive pulmonary disease (COPD) and periodontitis frequently coexist, but directionality and shared cellular mechanisms remain uncertain. We evaluated whether genetically proxied COPD liability is associated with periodontitis risk and explored candidate immune mechanisms.
We performed two-sample Mendelian randomization (MR) and smoking-adjusted multivariable MR (MVMR), followed by pathway enrichment and summary-data-based MR. Single-cell RNA sequencing (scRNA-seq) datasets from COPD peripheral blood and periodontitis gingiva were reanalyzed to localize implicated cell states. RAW264.7 macrophages were exposed to Porphyromonas gingivalis lipopolysaccharide (LPS, 1 μg/mL, 24 h) to assess candidate-gene responsiveness.
In univariable inverse-variance weighted MR, COPD liability was positively associated with chronic periodontitis (odds ratio [OR] 1.282, 95% confidence interval [CI] 1.097-1.499). The association persisted after adjustment for smoking initiation (OR 1.183, 95% CI 1.054-1.328) and past tobacco smoking (OR 1.235, 95% CI 1.101-1.387). The conditional F-statistic for COPD was 5.02 in the smoking-initiation model, requiring cautious interpretation. Enrichment implicated major histocompatibility complex class II antigen presentation and arachidonic-acid metabolism. HSP90AA1 and ALOX15B were prioritized as candidate protective mediators. Across separate cohorts, scRNA-seq signals converged on the monocyte-macrophage lineage. LPS reduced HSP90AA1 and ALOX15B transcript abundance in RAW264.7 cells.
The findings support a smoking-adjusted genetic association, not definitive smoking-independent causality. Macrophages and the two prioritized genes represent hypothesis-generating mediators that require validation in matched human cohorts and targeted perturbation models.
We performed two-sample Mendelian randomization (MR) and smoking-adjusted multivariable MR (MVMR), followed by pathway enrichment and summary-data-based MR. Single-cell RNA sequencing (scRNA-seq) datasets from COPD peripheral blood and periodontitis gingiva were reanalyzed to localize implicated cell states. RAW264.7 macrophages were exposed to Porphyromonas gingivalis lipopolysaccharide (LPS, 1 μg/mL, 24 h) to assess candidate-gene responsiveness.
In univariable inverse-variance weighted MR, COPD liability was positively associated with chronic periodontitis (odds ratio [OR] 1.282, 95% confidence interval [CI] 1.097-1.499). The association persisted after adjustment for smoking initiation (OR 1.183, 95% CI 1.054-1.328) and past tobacco smoking (OR 1.235, 95% CI 1.101-1.387). The conditional F-statistic for COPD was 5.02 in the smoking-initiation model, requiring cautious interpretation. Enrichment implicated major histocompatibility complex class II antigen presentation and arachidonic-acid metabolism. HSP90AA1 and ALOX15B were prioritized as candidate protective mediators. Across separate cohorts, scRNA-seq signals converged on the monocyte-macrophage lineage. LPS reduced HSP90AA1 and ALOX15B transcript abundance in RAW264.7 cells.
The findings support a smoking-adjusted genetic association, not definitive smoking-independent causality. Macrophages and the two prioritized genes represent hypothesis-generating mediators that require validation in matched human cohorts and targeted perturbation models.