AbstractAimEvidence from a Phase IIa trial showed that a complement C3‐targeted drug reduced gingival inflammation in patients with gingivitis. Using drug‐target Mendelian randomization (MR), we investigated whether genetically proxied C3 inhibition alters the risk of periodontitis.Materials and MethodsWe used multiple ‘cis’ instruments from the vicinity of the encoding loci of C3. Instrument selection was restricted to the drug target encoding loci (chromosome 19; 6,677,715–6,730,573 (GRCh37/hg19)). We selected three uncorrelated single‐nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) that were associated with serum C3 levels (p value <1 × 10⁻⁴) from a genome‐wide association study (GWAS) of 5368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse‐variance weighted meta‐analysis to estimate the odds ratio (OR) of the genetically proxied inhibition of C3 in relation to periodontitis.ResultsMR analysis revealed that the inhibition of C3 reduces the odds of periodontitis (OR 0.91 per 1 standard deviation reduction in C3; 95% confidence interval 0.87–0.96, p value = .0003).ConclusionsFindings from our MR analysis suggest a potential protective effect of C3 blockade against periodontitis.