AbstractBackgroundCirculating levels of interleukin‐17 (IL‐17) are associated with the presence and severity of periodontitis. However, whether IL‐17 is causal for disease development is unknown. We investigated the effect of genetically proxied IL‐17 on periodontitis using instrumental variable analysis.MethodsWe identified 12 genetic variants from genome‐wide association study (GWAS) of 7760 European descent individuals, used these variants as instrumental variables for IL‐17, and linked them to a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Generalized weighted least squares analysis accounted for linkage disequilibrium of variants.ResultsWe found an inverse association of genetically proxied IL‐17 and periodontitis (odds ratio, 0.84; 95% confidence interval: 0.75‒0.94; p = 0.003), which was corroborated after sensitivity analysis for horizontal pleiotropy.ConclusionThe findings suggest that IL‐17 protects against initial periodontitis.