MMP1、MMP9基因与慢性牙周炎的因果关系:基于两样本孟德尔随机化研究

doi:10.6040/j.issn.1671-7554.0.2025.0135

摘要/Abstract

摘要： 目的采用两样本孟德尔随机化(Mendelian randomization, MR)方法探索MMP1/MMP8/MMP9基因与慢性牙周炎是否存在因果关系。方法使用FinnGen R10(于2023年12月公开发布)慢性牙周炎(K11_PERIODON_CHRON)全基因组关联研究(genome-wide association study, GWAS)汇总数据,选择与暴露基因(MMP1/MMP8/MMP9)显著相关且符合标准的单核苷酸多态性作为工具变量,以MMP1/MMP8/MMP9基因作为暴露变量,慢性牙周炎作为结局变量。采用MR-Egger回归、加权中位数、逆方差加权、简单模式、加权模式进行MR分析。用Cochrans Q检验和MR-Egger回归进行异质性检测。用MR-Egger截距和MR-PRESSO分析方法评估水平多效性。并用leave-one-out分析方法评估MR分析结果的整体稳定性。使用比值比(odds ratio, OR)和95%置信区间(confidence interval, CI)来量化MMP1/MMP8/MMP9基因对慢性牙周炎的因果关系。结果在数据集ebi-a-GCST90012033(P=0.005, OR=0.955, 95%CI=0.924~0.986)和数据集eqtl-a-ENSG00000196611(P=0.048, OR=0.912, 95%CI=0.832~0.999)中,基于逆方差加权分析的结果提示MMP1基因预测的表达水平与慢性牙周炎风险之间存在显著的因果关系。在数据集prot-a-1920(P=0.087, OR=0.993, 95%CI=0.985~1.001)和数据集eqtl-a-ENSG00000118113(P=0.883, OR=0.992, 95%CI=0.887~1.109)中,基于逆方差加权分析的结果提示MMP8基因预测的表达水平与慢性牙周炎风险之间不存在显著的因果关系。在数据集prot-a-1921(P=0.450, OR=0.985, 95%CI=0.948~1.024)中,基于逆方差加权分析的结果提示MMP9基因预测的表达水平与慢性牙周炎风险之间不存在显著的因果关系。但在数据集eqtl-a-ENSG00000100985(P=2.405×10^-5, OR=1.123, 95%CI=1.064~1.184)中,基于逆方差加权分析的结果提示MMP9基因预测的表达水平与慢性牙周炎风险之间存在显著的因果关系。结论从遗传学层面,MR分析结果支持MMP1、MMP9基因在慢性牙周炎发病机制中可能发挥致病作用。从病因学层面,MMP1、MMP9基因只是慢性牙周炎的致病因素之一。

关键词: MMP1基因, MMP8基因, MMP9基因, 慢性牙周炎, 孟德尔随机化, 单核苷酸多态性, 因果关系

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

中图分类号:

R781.4+2

杨春桃,左玉. MMP1、MMP9基因与慢性牙周炎的因果关系:基于两样本孟德尔随机化研究[J]. 山东大学学报 (医学版), 2025, 63(11): 87-97.

YANG Chuntao, ZUO Yu. Causal relationship of MMP1 and MMP9 genes with chronic periodontitis: an exploratory study based on two-sample Mendelian randomization[J]. Journal of Shandong University (Health Sciences), 2025, 63(11): 87-97.

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