Circulating metabolites on dental caries risk: A Mendelian randomization study

To overcome the limitations of observational studies, this study aimed to systematically investigate the causal effects of a comprehensive panel of 1400 circulating serum metabolites on the risk of dental caries using a two-sample Mendelian randomization (MR) design. This two-sample MR study utilized genetic instruments for 1400 serum metabolites from a genome-wide association study of 8299 individuals. Genetic association data for dental caries were sourced from the FinnGen consortium (N = 500,348). The inverse-variance weighted method was the primary analysis, supplemented by extensive sensitivity analyses (e.g., MR-Egger, weighted median) to validate the MR assumptions and assess pleiotropy. The MR analysis identified 24 metabolites with a significant causal effect on dental caries. Genetically predicted higher levels of 16 metabolites were associated with increased risk, including sphingomyelin (d18:1/20:2, d18:2/20:1, d16:1/22:2) (odds ratio [OR] 1.091, 95% confidence interval [CI]: 1.030-1.156, P = .005) and flavin adenine dinucleotide (OR 1.046, 95% CI: 1.006-1.086, P = .023). Conversely, 8 metabolites were associated with a reduced risk, notably 5-methylthioadenosine (OR 0.923, 95% CI: 0.861-0.990, P = .025) and palmitoyl dihydrosphingomyelin (d18:0/16:0) (OR 0.923, 95% CI: 0.863-0.988, P = .021). Sensitivity analyses confirmed the robustness of these findings. This study provides evidence supporting a potential causal role for systemic metabolic and inflammatory processes in dental caries risk. These findings expand upon the traditional view of caries, suggesting it may also be influenced by the host's underlying metabolic state. The identified metabolites represent potential biomarkers for risk stratification and could be explored as targets for novel preventive interventions.