Abstract: Objective To investigate whether the MMP1/MMP8/MMP9 genes have a causal relationship with chronic periodontitis using a two-sample Mendelian randomization(MR)analysis. Methods Genome-wide association study(GWAS)was used to summarize data on chronic periodontitis(phenotype code: K11_PERIODON_CHRON)from the FinnGen R10 database(publicly available since December 2023). Single nucleotide polymorphisms significantly associated with exposure(MMP1/MMP8/MMP9 genes)and meeting the criteria were chosen as instrumental variables. The MMP1, MMP8 and MMP9 genes were defined as exposure variables and chronic periodontitis was defined as the outcome variable. MR analyses were performed using MR-Egger regression, weighted median, inverse variance weighted(IVW), weighted mode and simple mode methods. Heterogeneity was assessed using the Cochrans Q test and MR-Egger regression. Horizontal pleiotropy was evaluated using the MR-Egger intercept test and MR-PRESSO analysis. The general stability of the MR results was examined by leave-one-out analysis. The causal relationship between the MMP1/MMP8/MMP9 genes and chronic periodontitis was quantified using odds ratio(OR)and 95% confidence interval(CI). Results Based on inverse variance weighted(IVW)analysis, a significant causal relationship was observed between genetically predicted MMP1 expression and the risk of chronic periodontitis in the ebi-a-GCST90012033 dataset(P=0.005, OR=0.955, 95%CI=0.924-0.986)and the eqtl-a-ENSG00000196611 dataset(P=0.048, OR=0.912, 95%CI=0.832-0.999). In contrast, IVW results did not show a significant causal association between genetically predicted MMP8 expression and chronic periodontitis in the prot-a-1920 dataset(P=0.087, OR=0.993, 95%CI=0.985-1.001)and the eqtl-a-ENSG00000118113 dataset(P=0.883, OR=0.992, 95%CI=0.887-1.109). Similarly, no significant causal relationship was found between genetically predicted MMP9 expression and chronic periodontitis in the prot-a-1921 dataset(P=0.450, OR=0.985, 95%CI=0.948-1.024). Although IVW analysis based on the dataset eqtl-a-ENSG00000100985 yielded a statistically significant result(P=2.405×10^-5, OR=1.123, 95%CI=1.064-1.184), the general evidence consistently support a robust causal association between MMP9 expression and chronic periodontitis. Conclusion From a genetic point of view, the results of the MR analysis support a potential pathogenic role for MMP1 and MMP9 in the development of chronic periodontitis. From an etiological perspective, MMP1 and MMP9 may be contributing factors, although not exclusive, involved in the pathogenesis of chronic periodontitis.

Key words: MMP1 gene, MMP8 gene, MMP9 gene, Chronic periodontitis, Mendelian randomization, Single nucleotide polymorphisms, Causal relationship