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Illuminating the potential causality of serum level of matrix metalloproteinases and the occurrence of cardiovascular and cerebrovascular diseases: a Mendelian randomization study

Journal of Human Genetics volume 68, pages 615–624 (2023)Cite this article

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Abstract

Background

It is still not clear that whether the expression levels of matrix metalloproteinases (MMPs) family are associated with cardiovascular and cerebrovascular diseases (CCDs) in genetic level. We explored the causal role of 12 members of MMPs in CCDs with mendelian randomization (MR) method to facilitate further exploring the underlying mechanisms.

Methods

The relationship between MMPs and CCDs including intracerebral hemorrhage (ICH), hypertension, coronary heart disease (CHD), atrial fibrillation (AF), and outstanding risk factors of type II diabetes were determined with the inverse variance-weighted (IVW) method. The sensitivity analyses including MR-Egger regression, weighted median estimation, and MR pleiotropy residual sum and outlier were utilized to test the robustness of the results generated from the MR method.

Results

We found that a higher serum level of MMP-12 was related to a lower risk of ICH (OR = 0.8287, 95% CI: 0.7526–0.9125, p = 0.00013), but not hypertension, CHD, type II diabetes or AF. And our study also revealed that a higher serum level of MMP-8 could result in a lower risk of hypertension (OR = 0.9976, 95% CI: 0.9964–0.9988, p = 0.00012) and AF (OR = 0.9851, 95% CI: 0.9741–0.9963, p = 0.0092), but not ICH, CHD or type II diabetes. All other members of MMPs other than MMP-8 and MMP-12 showed no statistical association with CCDs according to this study. Sensitivity analyses confirmed the reliability of our results.

Conclusions

We provided statistical evidences for a potential causal relationship between MMP-12 and ICH, as well as MMP-8 and hypertension, while other MMPs showed weaker association with CCDs. The underlying mechanisms need to be established in the future.

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The original contributions presented in the study are in cluded in the article. Further inquiries can be directed to the corresponding author.

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Acknowledgements

We thank the Genetic Investigation of UK Biobank, FinnGen Consortium, MRC-IEU database, the MEGASTROKE GWAS dataset, and the International Stroke Genetics Consortium and all concerned investigators for sharing GWAS summary statistics on MMPs and CCDs.

Funding

This study was supported by the National Science & Technology Fundamental Resources Investigation Program of China to LZ (No. 2018FY100900), The Hunan Provincial Natural Science Foundation of China Grant to YZ (No. 2021JJ30923), The Provincial Science and Technology Innovation Leading Talents Project to LZ (No. 2021RC4014), National Clinical Research Center for Geriatric Disorders (XiangYa Hospital).

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Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China

    Xuelun Zou & Le Zhang

  2. Department of Pharmacy, Wuhan First Hospital, Wuhan, Hubei, P.R. China

    Leiyun Wang

  3. Department of Geriatrics, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P.R. China

    Yi Zeng

  4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China

    Le Zhang

  5. Multi-Modal Monitoring Technology for Severe Cerebrovascular Disease of Human Engineering Research Center, Xiangya Hospital, Central South University, Changsha, P.R. China

    Le Zhang

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Contributions

LZ and XZ designed the research and determined the structure of the paper. XZ, LX, and LW selected the references and contributed to the writing. XZ, LX, and LW helped to analyze the results of the study. LZ and YZ contributed to the revision and finalization of the article. All authors contributed to the article and approved the submitted version.

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Correspondence to Le Zhang.

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The authors declare no competing interests.

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Since this study was a retrospective study based on the public GWAS database as the published source, ethics approval was not required. Informed consent was obtained from all individual participants included in the public GWAS study.

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All data in this MR study were obtained from published GWAS studies, and the participants had signed informed consent in the published original GWAS study.

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Zou, X., Wang, L., Zeng, Y. et al. Illuminating the potential causality of serum level of matrix metalloproteinases and the occurrence of cardiovascular and cerebrovascular diseases: a Mendelian randomization study. J Hum Genet 68, 615–624 (2023). https://doi.org/10.1038/s10038-023-01154-0

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