Using human genetics to validate complement C3 as a drug target in periodontitis

AimEvidence from a phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. We investigated the therapeutic effect of genetically proxied C3 inhibition on periodontitis using drug target Mendelian randomization (MR). Materials and methodsWe used multiple cis instruments from the vicinity of the encoding loci of C3 that are associated with serum C3. We selected three independent single nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) from a genome-wide association study (GWAS) of 5,368 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. ResultsMR analysis revealed that the inhibition of C3 reduces the risk of periodontitis (Odds ratio 0.91 per 1 standard deviation reduction in C3; 95% Confidence Interval 0.87-0.96, P-value=0.0003). ConclusionsFindings from MR analysis showed that C3 blockade protects against periodontitis. Clinical relevanceO_ST_ABSScientific rationale for studyC_ST_ABSMounting evidence suggests that the complement system is dysregulated in periodontitis. First human randomized clinical trials demonstrated promising effects mediated via the blockade of C3, a key factor of the complement system. Results from drug target MR analysis can provide compelling evidence to predict the efficacy of pharmacological C3 blockage in future clinical trials in periodontitis patients. Principle findingsGenetically proxied C3 inhibition reduced periodontitis risk. Practical implicationsOur MR analysis provides genetic evidence that C3-targeted drugs might be an efficient adjunct therapy in periodontitis.