Causal relationship between matrix metalloproteinase and pulmonary embolism: a bidirectional two-sample Mendelian randomization study

Abstract

This study evaluated the causal relationship between matrix metalloproteinases (MMPs) and pulmonary embolism using data from the genome-wide association study (GWAS) of pulmonary embolism from the UK Biobank and a GWAS dataset of MMPs based on 5,457 Icelanders aged 65 years and older. MR-Egger, MR-PRESSO, Cochran's Q, and leave-one-out were used for sensitivity analysis. The Mendelian randomization (MR) analysis, based on the IVW analysis, indicated an elevated risk for pulmonary embolism in association with MMP19 (OR = 1.0009, 95%CI: 1-1.0017, P = 0.041), consistent with the weighted median method results (P = 0.015). In addition, despite the negative result from the IVW method (P = 0.554), the weighted median analysis suggested a reduced risk for pulmonary embolism related to MMP12 (OR = 0.9992, 95%CI: 0.9984-1, P = 0.038). No causal associations were found for the other MMPs (including MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP13, MMP14, MMP16, MMP17, and MMP20) on pulmonary embolism (all P > 0.05). The reverse MR analysis revealed no causal associations between pulmonary embolism as exposure and MMPs as outcomes. Sensitivity analyses confirmed the robustness of these findings. In conclusion, this MR analysis revealed the potential causal relationship between MMPs and pulmonary embolism, suggesting that measuring MMPs could help identify people at higher risk of pulmonary embolism, but further research is needed.

Keywords: Causality; Genome-wide association study; Matrix metalloproteinase; Mendelian randomization; Pulmonary embolism.

Fig. 1

Study design and workflow.

Fig. 2

Scatter plot of SNP effects on matrix metalloproteinase and pulmonary embolism. The 95% CI for the effect size on pulmonary embolism is shown as vertical lines, while the 95% CI for the effect size on matrix metalloproteinase is shown as horizontal lines. The slope of fitted lines represents the estimated MR effect per method. (A) MMP12. (B) MMP19.

Fig. 3

Forest plot showing results from the Mendelian randomization analysis. (A) MMP12. (B) MMP19.

Fig. 4

Funnel plot showing the estimation using the inverse of the standard error of the causal estimate with each individual SNP as a tool. The vertical line represents the estimated causal effect. SNP, single nucleotide polymorphism. (A) MMP12. (B) MMP19.

Fig. 5

Leave-one-out sensitivity analysis, where each SNP was iteratively removed from the instrumental variables. (A) MMP12. (B) MMP19.