Adiposity, Not Galectin-3, Is the Independent Causal Driver of Periodontitis: A Multivariable Mendelian Randomization Study

Objectives: Using Mendelian randomization (MR) to evaluate the causal relationships among circulating galectin-3 (Gal-3), obesity, and periodontitis, and to determine whether Gal-3 is an independent risk factor or a downstream metabolic biomarker. Materials and methods: Univariable Mendelian randomization (UVMR) was performed using genetic instruments for circulating Gal-3 (n = 21,758) and periodontitis (FinnGen R11, 24,570 cases and 390,928 controls). Multivariable Mendelian randomization (MVMR) was applied with adjustment for Body Mass Index (BMI) and Type 2 Diabetes Mellitus (T2DM). Finally, reverse Mendelian randomization was conducted to assess upstream causal effect of BMI on circulating Gal-3 levels. Results: In univariate Mendelian randomization, genetically predicted Gal-3 is nominally associated with increased risk of periodontitis (OR = 1.031, 95% CI: 1.003–1.059, P = 0.029). However, in multivariate Mendelian randomization adjusted for BMI and T2DM, direct effect of Gal-3 on periodontitis is diminished (OR = 1.017, 95% CI: 0.986–1.049, P = 0.277), while BMI retains robust independent causal effect (OR = 1.075, 95% CI: 1.027–1.126, P = 0.002). Reverse Mendelian randomization indicates suggestive positive causal direction: BMI increases levels of circulating Gal-3 (OR = 1.058, 95% CI: 0.998–1.121, P = 0.057). Conclusions: Periodontitis is not independently causally related to circulating Gal-3. Association is mostly because of obesity-related confounding factors, meaning Gal-3 is downstream biomarker of systemic metabolism dysfunction as opposed to a periodontal pathogen. Clinical relevance: In patients with metabolic needs, periodontal prevention and treatment must be based on weight control and obesity, but not be focused on downstream Gal-3 mechanism.