Exploring the causal relationship between MMPs and breast cancer risk： a Mendelian randomization study

doi:10.3969/j.issn.1009-976X.2024.03.004

Abstract

Abstract: Objective To explore the causal relationships between various subtypes of matrix metalloproteinases （MMPs） and the risk of developing breast cancer. Methods Using 501 428 genetic variants related to plasma MMPs levels from 990 Europeans in the publicly available MRC-IEU database as instrumental variables for exposure, and 19 674 639 genetic variants from 201 633 breast cancer patients in the FinnGen version 10 database as instrumental variables for outcome, we conducted a two-sample bidirectional Mendelian randomization analysis. The inverse variance weighted method was used as the primary analysis, with MR-Egger regression, simple mode method, weighted median method, and weighted mode method as secondary complementary regression models. Sensitivity analysis was performed using Cochran's Q test to verify the reliability of the results, MR-Egger test to assess the horizontal pleiotropy of instrumental variables, and leave-one-out analysis to evaluate the potential influence of single nucleotide polymorphisms on the results. Results Impact of MMPs on breast cancer： The inverse variance weighted method detected a reverse causal relationship between MMP-7 expression levels and the risk of breast cancer （OR=0.95, 95%CI： 0.92-0.99, P<0.05）; no statistically significant association was found between the expression levels of other MMPs and the risk of breast cancer. Meta-analysis showed no statistically significant association between overall plasma MMPs and the risk of breast cancer. Impact of breast cancer on MMPs： The inverse variance weighted method showed no statistically significant association between the risk of breast cancer and the expression levels of MMPs. Conclusion The overall effect of MMPs does not have a significant impact on the occurrence and development of breast cancer. However, there is a negative causal relationship between MMP-7 expression levels and the risk of breast cancer. As MMP-7 expression levels decrease, the risk of breast cancer increases. MMP-7 may be a protective factor closely related to the occurrence and progression of breast cancer among MMPs and should be paid more attention.

Key words: breast carcinoma, MMPs, mendelian randomization study

摘要： 目的探讨不同分型的基质金属蛋白酶（MMPs）与乳腺癌患病风险的因果关系。方法以公开发表的MRC-IEU数据库中990名欧洲人的501 428个与血浆MMPs水平相关的基因变异作为反映暴露水平的工具变量,并以FinnGen第10版数据库中201 633名乳腺癌患者的19 674 639个基因变异作为反映结局水平的工具变量,对二者进行双样本双向孟德尔随机化分析,以逆方差加权法作为主要分析方法,以MR-Egger回归、简单模式法、加权中位数法和加权模式法作为次要补充回归模型,计算不同分型的MMPs与乳腺癌之间的因果关系。采用Cochran's Q检验进行敏感性分析验证结果的可靠性,使用MR-Egger截距检验评估工具变量的水平多效性,使用留一法评估结果是否存在具有潜在影响的单核苷酸多态性。结果 MMPs对乳腺癌的影响：逆方差加权法检测结果显示,MMP-7的表达水平与乳腺癌发病风险呈反向因果关联（OR=0.95,95%CI：0.92~0.99,P<; 0.05）;其余MMPs的表达水平与乳腺癌的发病风险未存在统计学上的关联,Meta分析显示,血浆MMPs的整体效应与乳腺癌的发病风险未存在统计学上的关联。乳腺癌对MMPs的影响：逆方差加权法检测显示,乳腺癌的发病风险与MMPs的表达水平未存在统计学上的关联。结论 MMPs的整体效应未对乳腺癌的发生发展有明显的影响,但是MMP-7的表达水平与乳腺癌的发病风险之间存在负向因果关系,随着MMP-7 的表达水平降低,乳腺癌的发病风险升高,MMP-7可能是MMPs中与乳腺癌发病及进展密切相关的保护因子,应给予更多的关注。

关键词: 乳腺癌, MMPs, 孟德尔随机化

CLC Number:

R737.9

HAN Zhi-ren, ZHU Xiang-ping, HAN Bei-nan, WENG Hai-yan, YANG Qiong. Exploring the causal relationship between MMPs and breast cancer risk： a Mendelian randomization study[J]. Lingnan Modern Clinics In Surgery, 2024, 24(03): 162-174.

韩稚人, 朱祥平, 韩北南, 翁海燕, 杨琼. 以孟德尔随机化探究MMPs与乳腺癌的因果关系[J]. 岭南现代临床外科, 2024, 24(03): 162-174.

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