Systematic druggable genome-wide Mendelian randomization identifies therapeutic target genes for chronic periodontitis

Currently,the treatment of chronic periodontitis (CP) still has challenges. This study aimed to identify novel drug targets for the treatment of chronic periodontitis in the druggable genome using the Mendelian randomization (MR) method.In this study,based on the list of 4479 drug gene targets,overlapping genes were selected in blood expression Quantitative Trait Loci(eQTL), which were then subjected to Two-Sample MR(TSMR) and validated Fusion Transcriptome-Wide Association Study(TWAS) with data from the Genome-Wide Association Study(GWAS) of CP to confirm drug genes genetically associated with CP and tested for multiplicity of effects using Summary-data-based Mendelian randomization(SMR) analysis and colocalisation. Finally, Phenome-Wide association study(PheWAS) was executed on the identified drug targets.We applied SMR,TSMR,Fusion TWAS,and a series of manners of co-localisation to assess the genetic association between drugable targets and CP. In conclusion,Metalloproteinase 25(MMP25)was considered the most promising drug target,in addition to which we maintained some confidence in TNFRSF18,CDC25B,STK10 and ACVR2B.Finally,the PheWAS-MR results showed that the possible side effects of applying MMP25 inhibitors were Otitis externa as well as some metabolic disorders,among others.In summary,we identified five potential CP drug targets using TSMR,Fusion TWAS,SMR,and co-localisation a series of methods,of which MMP25 passed all the tests.Such discovery offered an academic basis for future CP drug development and reduce drug development time and economic costs to some extent.