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. 2025 Apr 30;17(4):2377-2385.
doi: 10.21037/jtd-2025-377. Epub 2025 Apr 27.

Causal relationship between serum metalloproteinase 12 levels and aortic dissection and aortic aneurysm: a bidirectional Mendelian randomization study

Xiaoyan Feng  1 , Shoulei Chen  1 , Tao Liu  1 , Hexi Huang  1 , Giovanni Mariscalco  2 , Carlos A Mestres  3 , Marcus Taylor  4 , Ken Nakamura  5 , Baoshi Zheng  1
Affiliations

Causal relationship between serum metalloproteinase 12 levels and aortic dissection and aortic aneurysm: a bidirectional Mendelian randomization study

Xiaoyan Feng et al. J Thorac Dis. .

Abstract

Background: Elevated matrix metalloproteinase-12 (MMP-12) levels have been shown to be elevated in patients with aortic dissection (AD) and aortic aneurysm (AA). However, whether MMP-12 is associated with AD and AA has not been conclusively examined. The aim of this study was to clarify the role of MMP-12 in AD and AA formation and to verify the correlation between MMP-12 and AD and AA development at the gene level via Mendelian randomization (MR) analysis.

Methods: The data for analyzing MMP-12 gene mutations were obtained from the Integrative Epidemiology Unit (IEU) OpenGWAS database, which includes data from 21,758 European residents. Data on the genetic variation of AD and AA were retrieved from the FinnGen database. In the forward MR analysis, we evaluated the causal effect of MMP-12 on AD and AA. Subsequently, the causal association of AD and AA with MMP-12 was investigated in the reverse MR study. The inverse-variance weighting (IVW) method was the principal statistical technique used in this study.

Results: In the forward MR analysis, the IVW results showed that serum MMP-12 levels were positively related to an increased risk of AD [odds ratio (OR) =1.301; 95% confidence interval (CI): 1.002-1.697; P=0.048] and AA (OR =1.121; 95% CI: 1.007-1.248; P=0.04). For the reverse MR studies, no genetic relationships were observed between AD or AA and MMP-12 levels, nor was any heterogeneity or pleiotropy.

Conclusions: There was a correlation between serum MMP-12 and the risk of AD and AA. MMP-12 may be a potential therapeutic target for AD and AA.

Keywords: Matrix metalloproteinase-12 (MMP-12); Mendelian randomization (MR); aortic aneurysm (AA); aortic dissection (AD).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-377/coif). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Study design of the bidirectional MR study on the association of serum MMP-12 levels with AD and AA. The black lines mean positive MR. The exposure is MMP-12 and the outcome is AD/AA. The red lines mean reverse MR. The exposures are AD/AA and the outcome is MMP-12. AA, aortic aneurysm; AD, aortic dissection; IV, instrumental variable; MMP-12, matrix metalloproteinase-12; MR, Mendelian randomization.
Figure 2
Figure 2
Associations of serum MMP-12 levels with AD and AA. MMP-12 was found to be a potential risk factor for AD and AA. AA, aortic aneurysm; AD, aortic dissection; CI, confidence interval; MMP-12, matrix metalloproteinase-12; MR, Mendelian randomization; nSNP, nonsynonymous single-nucleotide polymorphism; OR, odds ratio; PRESSO, pleiotropy residual sum and outlier.
Figure 3
Figure 3
Scatter plots of the causal effect of MMP-12. (A) The scatter plot of the causal effect of MMP-12 on AD. (B) The scatter plot of the causal effect of MMP-12 on AA. AA, aortic aneurysm; AD, aortic dissection; MMP-12, matrix metalloproteinase-12; MR, Mendelian randomization; SNP, single-nucleotide polymorphism.
Figure 4
Figure 4
Causal effects of AD and AA on serum MMP-12 levels. No genetic associations were observed for AD or AA with serum MMP-12 levels. AA, aortic aneurysm; AD, aortic dissection; CI, confidence interval; MMP-12, matrix metalloproteinase-12; MR, Mendelian randomization; nSNP, nonsynonymous single-nucleotide polymorphism; OR, odds ratio; PRESSO, pleiotropy residual sum and outlier.
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