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Causal associations of circulating Helicobacter pylori antibodies with stroke and the mediating role of inflammation

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Abstract

Background

Observational studies have shown that Helicobacter pylori (H. pylori) infection and H. pylori antibodies are associated with an increased risk of stroke. However, which and how H. pylori antibodies serve as the causal determinant of the development of stroke remains largely unknown.

Methods

Genome-wide association studies (GWAS) on seven different antibodies of H. pylori-specific proteins, stroke, and stroke subtypes were included in this study. Mendelian randomization (MR) and multivariable MR (MVMR) analysis were performed to assess the causal associations between H. pylori antibodies and the development of stroke and to determine the potential mechanisms underlying the associations.

Results

Genetically predicted serum H. pylori vacuolating cytotoxin-A (VacA) antibody level was associated with an increased risk of all-cause stroke (odds ratio [OR] = 1.04, 95% CI 1.01–1.07, P = 0.017) and cardioembolic stroke (CES, OR = 1.11, 95% CI 1.04–1.18, P = 0.001). The results of multivariable MR (MVMR) showed that C-reactive protein (CRP), but not monocyte chemoattractant protein-1 and peptic ulcer, mediated the causal effects of VacA-positive H. pylori infection on all-cause stroke and CES. No strong causal associations were found between other H. pylori antibodies and stroke and its subtypes.

Conclusions

Our results demonstrate that H. pylori VacA antibody is the only causal determinant associated with the risk of stroke in the spectrum of H. pylori-related antibodies, in which CRP may mediate the association. This study suggests that inhibition of the CRP signaling pathway may reduce the risk of stroke in patients with VacA-positive H. pylori infection.

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Data availability

The GWAS summary statistics data used in this MR study is available in OpenGWAS (https://gwas.mrcieu.ac.uk/) and Catalog GWAS (https://www.ebi.ac.uk/gwas/home/).

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Acknowledgements

The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. The authors thank all the participants, investigators, and consortiums who contributed to this study.

Funding

This study was supported by the Project for Sanqin Academic Innovation Team in Shaanxi Province (SQ0157) and the Fundamental Research Funds for the Central Universities, Xi’an Jiaotong University (XZY012022136). The funding agency had no role in the design, implementation or interpretation of this study.

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Authors and Affiliations

  1. Department of Geriatric Neurology, Shaanxi Provincial People’s Hospital, No. 256, Youyi West Road, Xi’an, 710068, Shaanxi, People’s Republic of China

    Xingzhi Guo, Peng Tang, Xin Zhang & Rui Li

  2. Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Xi’an, 710068, Shaanxi, People’s Republic of China

    Xingzhi Guo, Peng Tang, Xin Zhang & Rui Li

  3. Institute of Medical Research, Northwestern Polytechnical University, Xi’an, 710072, Shaanxi, People’s Republic of China

    Xingzhi Guo & Rui Li

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  1. Xingzhi Guo
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Contributions

X.G. and R.L. conceived and designed the project. X.G., P.T., and X.Z. collected and analyzed the data. X.G. and P.T. drafted the manuscript. R.L. revised the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Rui Li.

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Conflict of interest

The authors have no conflicts of interest relevant to this article to disclose.

Ethics approval

There were no patients directly involved in the overall process of our study. This study was performed based on publicly available data and no separate ethical approval was required. All human studies included in this analysis were conducted according to the Declaration of Helsinki.

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All authors have read, validated the accuracy of the data, and approved the final manuscript.

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Supplementary Information

Below is the link to the electronic supplementary material.

11_2023_1740_MOESM1_ESM.xlsx

Supplementary file1 (XLSX 97 KB) Supplementary data sheet. List of harmonized instrumental variables for each exposure-outcome pair used in MR analysis.

Supplementary file2 (DOCX 1712 KB)

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Guo, X., Tang, P., Zhang, X. et al. Causal associations of circulating Helicobacter pylori antibodies with stroke and the mediating role of inflammation. Inflamm. Res. 72, 1193–1202 (2023). https://doi.org/10.1007/s00011-023-01740-0

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  • DOI: https://doi.org/10.1007/s00011-023-01740-0

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