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Causal effect of serum matrix metalloproteinase levels on venous thromboembolism: a Mendelian randomization study
Deheng Han1, Fangcong Yu1, Liangrong Zheng1
1Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Objectives:
Serum matrix metalloproteinase (MMP) levels are associated with cardiovascular diseases. However, the causal associations between serum levels of specific MMPs and venous thromboembolism (VTE) remain unclear. The present study sought to explore the causal relationship between serum MMP levels and VTE by using the Mendelian randomization (MR) method.
Methods:
In this study 2-sample MR study, the exposure data on serum MMP levels were derived from genome-wide association studies involving 21,758 individuals from 13 cohorts of European descent. The outcome data on VTE, including deep vein thrombosis and pulmonary embolism, were derived from the FinnGen research project. The primary method used was the inverse-variance weighting method. The MR-Egger intercept test and the Cochran Q test were used to evaluate pleiotropy and heterogeneity.
Results:
Using the inverse-variance weighting method, higher serum MMP-12 levels were found to be associated with an increased risk of VTE (odds ratio, 1.04; 95% confidence interval, 1.01 to 1.07; p=0.001). Moreover, there was a weak association between the levels of certain MMPs and VTE. Sensitivity analyses revealed no significant heterogeneity and pleiotropy in our study, and the Steiger directionality test did not reveal a significant reverse causation association.
Conclusions:
There is a causal association between MMP-12 levels and VTE, which may have substantial implications for the diagnostic and therapeutic strategies used for VTE.
Insights
Higher serum matrix metalloproteinase-12 (MMP-12) levels causally increase the risk of venous thromboembolism (VTE). This finding suggests MMP-12 may be a target for VTE diagnostics and therapeutics.
Area of Science:
- Cardiovascular Research
- Genetics
- Biochemistry
Background:
- Serum matrix metalloproteinase (MMP) levels are linked to cardiovascular diseases.
- The causal relationship between specific MMPs and venous thromboembolism (VTE) is not well-established.
Purpose of the Study:
- To investigate the causal association between serum MMP levels and VTE using Mendelian randomization (MR).
Main Methods:
- A 2-sample MR study utilized genome-wide association study data for serum MMP levels (n=21,758) from European cohorts.
- VTE outcome data were sourced from the FinnGen research project.
- Inverse-variance weighting was the primary analysis method, with MR-Egger and Cochran Q tests for pleiotropy and heterogeneity.
Main Results:
- Elevated serum MMP-12 levels were significantly associated with an increased risk of VTE (OR, 1.04; 95% CI, 1.01-1.07; P=0.001).
- Sensitivity analyses confirmed no significant heterogeneity or pleiotropy.
- The Steiger directionality test ruled out significant reverse causation.
Conclusions:
- A causal link exists between serum MMP-12 levels and VTE.
- MMP-12 may represent a novel target for VTE diagnostic and therapeutic strategies.
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