Periodontal disease is associated with increased stroke risk, an association partially mediated by inflammation.

Despite evidence linking periodontal disease to stroke risk, research investigating the potential mediating role of inflammatory markers and the modifying influence of genetic susceptibility in this relationship remains limited. The study aimed to assess the association between self-reported high risk of periodontal disease and stroke, while exploring the potential mediating effects of inflammatory markers and the modifying influence of genetic susceptibility. Using UK Biobank data, we investigated the association between high risk of periodontal disease and incident stroke using Cox proportional hazards regression models. Participants were classified as having a high risk of periodontal disease if they reported experiencing any of painful gums, bleeding gums, and/or loose teeth. We explored the potential mediating role of inflammatory markers in the observed association through mediation analyses. For genetic analyses, we calculated a genetic risk score (GRS) for stroke using 32 single nucleotide polymorphisms, stratified participants into tertiles, and conducted interaction analyses between GRS and periodontal disease risk with respect to both all stroke and ischemic stroke. The study included 442,648 participants, followed up for a median of 13.7 years. Participants with a high risk of periodontal disease showed significantly increased risk of all stroke (HR = 1.11, 95%CI: 1.05 - 1.16) and ischemic stroke (HR = 1.11, 95%CI: 1.05 - 1.18) after adjusting for confounders, but no significant associations were found for hemorrhagic stroke (HR = 1.08, 95%CI: 0.98 - 1.19). Mediation analyses showed that inflammatory markers partially mediated this relationship, with mediation effects ranging from 0.86% to 8.41% for all stroke and 1.03% to 9.58% for ischemic stroke. Genetic analyses revealed no significant interaction between high risk of periodontal disease and stroke GRS concerning the all stroke risk, but a significant interaction was found for ischemic stroke, with participants having both periodontal disease risk and a high GRS showing the highest risk (HR = 1.19, 95%CI: 1.07 - 1.32). This study demonstrates a significant association between high periodontal disease risk and increased stroke risk, particularly ischemic stroke, with partial mediation by inflammatory markers and interaction with genetic risk factors.