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Genetic Evidence Supporting a Causal Association Between mTOR-Dependent EIF-4E Circulating Protein Level and Osteoporosis

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Abstract

Introduction

The mechanistic target of rapamycin (mTOR) regulates bone homeostasis, a crucial factor in osteoporosis (OP) development. However, most research is based on observational studies, and the causality remains uncertain. Therefore, we analyzed two samples of mendelian randomization (MR) to determine whether there is a causal relationship between mTOR-dependent circulating proteins and OP.

Methods

Mendelian weighting (weighted median [WM], inverse variance weighting [IVW], and MR-Egger regression) were applied to analyze the causality between bone phenotypes (bone mineral density [BMD] in forearm, femoral neck, lumbar spine, and heel) and mTOR-dependent circulating proteins (RP-S6K, 4EBP, EIF-4E, EIF-4A, and EIF-4G). Horizontal pleiotropy and heterogeneities were detected using Cochran’s Q test, MR-Pleiotropy RE-Sidual Sum and Outlier (MR-PRESSO), and “leave-one-out” analysis. The proteomics-GWAS INTERVAL study was used to select the instrumental variables (IVs) for mTOR proteins.

Results

As phenotypes for OP, estimations of BMD were taken in four different sites: forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). Based on IVW analysis, EIF4E is causally related to FA-BMD (OR = 0.938, 95% CI 0.887, 0.991, p = 0.024) but not to BMD elsewhere.

Conclusion

MR analysis revealed a causal relationship between EIF-4E and FA-BMD, which may provide new insights into the underlying pathogenesis of OP and a new therapeutic target for OP.

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Data Availability

These data were derived from the following resources available in the public websites: the exposure data for mTOR-dependent circulating proteins (https://www.phpc.cam.ac.uk/ceu/proteins/), and the outcome data for BMD (https://gwas.mrcieu.ac.uk/datasets/).

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Acknowledgements

We are grateful to the GEFOS for BMD GWAS summary statistics and the proteomics-GWAS INTERVAL study for releasing the mTOR-dependent circulating proteins summary statistics.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82001740), the Natural Science Foundation of Shanxi Province (No. 202203021221269), and the Graduate Education Innovation Program of Shanxi Province (2021Y357). The journal’s Rapid Service Fee was funded by the authors.

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Author notes

  1. Ting Cheng and Yao-Chen Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China

    Ting Cheng, Xiao-Feng Li & Sheng-Xiao Zhang

  2. Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China

    Ting Cheng, Yao-Chen Zhang, Ke-Yi Fan, Jing-Xi Hu, Qian Wang, Liu Liu, He-Yi Zhang, Yao-Pu Hou, Xiao-Feng Li & Sheng-Xiao Zhang

  3. Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi, China

    Ting Cheng, Yao-Chen Zhang, Ke-Yi Fan, Jing-Xi Hu, Qian Wang, Qi Wang, Liu Liu, He-Yi Zhang, Yao-Pu Hou, Xiao-Feng Li & Sheng-Xiao Zhang

  4. School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China

    Qi Wang

  5. Shanxi Key Laboratory of Big Data for Clinical Decision Research, Taiyuan, China

    Qi Wang

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Contributions

Ting Cheng and Yao-Chen Zhang: Methodology, Software, Writing-Original Draft; Ke-Yi Fan: Investigation; Jing-Xi Hu and Qian Wang: Visualization; Qi Wang, Liu Liu, He-Yi Zhang, Yao-Pu Hou: Data Curation; Xiao-Feng Li: Conceptualization; Sheng-Xiao Zhang: Supervision, Writing- Review & Editing. This article is authored by individuals who meet the International Committee of Medical Journal Editors (ICMJE) criteria, take responsibility for the authenticity of the work, and have provided their consent for the publication of this version.

Corresponding author

Correspondence to Sheng-Xiao Zhang.

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Conflict of Interest

Ting Cheng, Yao-Chen Zhang, Ke-Yi Fan, Jing-Xi Hu, Qian Wang, Qi Wang, Liu Liu, He-Yi Zhang, Yao-Pu Hou, Xiao-Feng Li, Sheng-Xiao Zhang have no conflicts of interest to disclose.

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The study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Patient consent for this study was not necessary because the study was non-interventional and data were de-identified.

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Cheng, T., Zhang, YC., Fan, KY. et al. Genetic Evidence Supporting a Causal Association Between mTOR-Dependent EIF-4E Circulating Protein Level and Osteoporosis. Adv Ther 40, 4987–4998 (2023). https://doi.org/10.1007/s12325-023-02676-x

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