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Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study

  • Author Footnotes
    a Contributed equally to this study.
    Y. Zhang
    Footnotes
    a Contributed equally to this study.
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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  • Author Footnotes
    a Contributed equally to this study.
    D. Li
    Footnotes
    a Contributed equally to this study.
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Department of Spine Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
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  • Author Footnotes
    a Contributed equally to this study.
    Z. Zhu
    Footnotes
    a Contributed equally to this study.
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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  • S. Chen
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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  • M. Lu
    Affiliations
    Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
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  • P. Cao
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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  • T. Chen
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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  • S. Li
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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  • S. Xue
    Affiliations
    Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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  • Y. Zhang
    Affiliations
    Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
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  • J. Zhu
    Affiliations
    Department of Orthopedics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
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  • G. Ruan
    Correspondence
    Address correspondence and reprint requests to: Guangfeng Ruan, 253 Industrial Avenue Central, Guangzhou City 510000, Guangdong Province, China.
    Affiliations
    Clinical Research Centre, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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  • C. Ding
    Correspondence
    Address correspondence and reprint requests to: Changhai Ding, 253 Industrial Avenue Central, Guangzhou City 510000, Guangdong Province, China.
    Affiliations
    Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
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  • Author Footnotes
    a Contributed equally to this study.

      Summary

      Objective

      To provide some causal evidence concerning the effects of metformin on osteoarthritis (OA) using two metformin targets, namely AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15) as metformin proxies.

      Methods

      This is a 2-sample Mendelian randomization design. We constructed 44 AMPK-related variants genetically predicted in HbA1c (%) as instruments for AMPK and five variants strongly predicted GDF-15 as instruments for GDF-15. Summary-level data for three OA phenotypes, including OA at any site, knee OA, and hip OA were obtained from the largest genome-wide meta-analysis across the UK Biobank and arcOGEN with 455,211 Europeans. Main analyses were conducted using the inverse-variance weighted method. Weighted median and MR-Egger were conducted as sensitivity analyses to assess the robustness of our results.

      Results

      Genetically predicted AMPK were negatively associated with OA at any site (OR: 0.60; 95% CI: 0.43–0.83) and hip OA (OR: 0.42; 95% CI: 0.22–0.80), but with not knee OA (OR: 0.85; 95% CI: 0.49–1.50). Higher levels of genetically predicted GDF-15 reduced the risk of hip OA (OR: 0.95; 95% CI: 0.90–0.99), but not OA at any site (OR: 1.00; 95% CI: 0.98–1.02) and knee OA (OR: 1.02; 95% CI: 0.98–1.07).

      Conclusion

      This study indicates that AMPK and GDF-15 can be potential therapeutic targets for OA, especially for hip OA, and metformin would be repurposed for OA therapy which needs to be verified in randomized controlled trials.

      Keywords

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