Complement C3 as a potential drug target in periodontitis: Evidence from the cis-Mendelian randomization approach

Aim: Evidence 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 Methods:We 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 x 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.Results: MR 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).Conclusions: Findings from our MR analysis suggest a potential protective effect of C3 blockade against periodontitis.