Oral health and periodontal inflammation have repeatedly been identified as contributors to cardiovascular and inflammatory disease in epidemiological studies and interventional trials evaluating surrogate parameters (1). Conversely, there is evidence that systemic diseases such as type 2 diabetes can promote periodontal inflammation, indicating a bidirectional relationship (2, 3). Interestingly, while the majority of studies have examined how oral conditions may influence systemic inflammation, the potential contribution of generalized, low-grade systemic inflammation to oral health has received relatively little attention. Importantly, the relationship between systemic inflammation and oral health has not been explored in large-scale genomic studies, although genetic approaches may help to clarify whether observed associations are consistent with a directional influence. Accordingly, this study aimed to investigate whether genetic variants that diminish IL-6 signaling and thereby lower systemic inflammatory activity are associated with improved oral health. To this end we used a genotype-based approach focusing on a well-characterized functional single-nucleotide polymorphism (SNPs) in the IL-6 receptor pathway.

Data from 468,460 participants of the UK Biobank with available information on self-reported oral health indicators and high-sensitivity C-reactive protein (hsCRP) plasma levels were analysed (4). Self-reported oral health indicators included tooth loss, denture use, bleeding gums, loose teeth, mouth ulcers and toothache (i.e. summarized as oral health indicators). Of note, these questionnaire-based indicators do not reflect formal clinical diagnoses but represent participants’ subjective experience of oral health burden. The questionnaire was completed during the baseline assessment of each participant. In addition, the genetic IL6 receptor variant p.Asp358Ala (rs2228145), which has been demonstrated to be linked to impaired IL-6 receptor signaling and reduced subclinical inflammation as measured by hsCRP was used to examine whether genetically influenced differences in inflammatory tone are accompanied by differences in self-reported oral health indicators (5). Logistic regression models were adjusted for age, sex, body mass index (BMI), hsCRP, smoking status, and socio-economic indicators (including income and educational attainment). Model residuals fulfilled assumptions of normality. Use of data for this study was approved by the UK Biobank (application number 88924).

Stratification of hsCRP plasma levels into tertiles (hsCRP_1st: 0.49mg/L [0.08-0.84] hsCRP_2nd: 1.33mg/L [0.84-2.11] hsCRP_3rd: 3.85mg/L [2.11-79.96]) demonstrated expected associations between systemic inflammatory state and cardiovascular disease (all p < 0.001; Table 1). Higher hsCRP tertiles were also associated with a greater prevalence of adverse self-reported oral health indicators (1^st vs. 3^rd: 35% vs. 45%; p < 0.001) including denture use (1^st vs. 3^rd: 12% vs. 21%; p < 0.001) and loose teeth (1^st vs. 3^rd: 3.2% vs. 5.6%; p < 0.001; Table 1). To explore whether genetically influenced differences in IL-6 signaling show patterns consistent with these associations, we examined the SNP p.Asp358Ala (rs2228145) linked to impaired IL-6 signaling (5). Carriers of the C/C variant, exhibited a 18% decrease in hsCRP levels compared to carriers of the A/A variant (A/A: 2.77±4.52 mg/L vs. C/C: 2.29±4.00mg/L; p < 0.001; Figure 1A). Furthermore, logistic regression indicated that presence of the C/C variant was associated with lower odds of the self-reported oral health composite endpoint (OR 0.98, 95%CI 0.96–0.99, p=0.007). Exploratory endpoint analyses showed reduced odds for toothache (OR 0.93, 95%CI 0.89–0.97, p=0.0003), bleeding gums (OR 0.97, 95%CI 0.95–1.00, p=0.035), and loose teeth (OR 0.95, 95%CI 0.91–0.99, p=0.015), whereas associations with denture use (OR 1.01, 95%CI 0.91–0.99, p=0.45) and mouth ulcers (OR 1.00, 95%CI 0.97–1.03, p=0.83) were neutral (Figure 1B).

In a large-scale population analysis from the UK Biobank, we show that genetically determined attenuation of IL-6 signaling via the IL6R p.Asp358Ala variant is associated with improved self-reported composite indices of oral health. These data suggest that systemic inflammation may be a driver of oral pathologies and challenge the prevailing concept that poor oral health contributes unidirectionally to systemic inflammation. Further, they provide a framework for future studies that employ clinically validated oral health outcomes, longitudinal designs, and formal causal inference approaches to clarify underlying mechanisms and determine their potential clinical relevance.

A key limitation of our work is the reliance on self-reported oral health data in the UK Biobank. While such measures cannot replace clinical diagnoses, selected items—particularly tooth loss, loose teeth, and gingival bleeding—have demonstrated acceptable validity for population-level surveillance of periodontitis (6, 7). Nevertheless, oral health indices in our study represent general oral health burden, recognizing that items such as toothache, denture use, or mouth ulcers may arise from heterogeneous or non-periodontal conditions. While these limitations apply, the aim of this manuscript was to focus on the association between oral health and inflammation; phenotypic precision, disease staging, and subclinical characterization lie beyond its scope. In addition, although the IL6R p.Asp358Ala variant is known to attenuate IL-6 signaling, it concomitantly increases circulating soluble IL-6, potentially eliciting pleiotropic downstream effects that were not assessed in the present analysis.

In conclusion, here we demonstrate that the genetic variant IL6R p.Asp358Ala is associated with improved self-reported composite indices of oral health and implies a bidirectional relationship between oral pathologies and inflammation.