Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study,Osteoarthritis and Cartilage

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Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study
Osteoarthritis and Cartilage ( IF 7.2 ) Pub Date : 2022-07-06 , DOI: 10.1016/j.joca.2022.06.010
Y Zhang ₁ , D Li ₂ , Z Zhu ₁ , S Chen ₁ , M Lu ₃ , P Cao ₁ , T Chen ₁ , S Li ₁ , S Xue ₄ , Y Zhang ₅ , J Zhu ₆ , G Ruan ₇ , C Ding ₈

Affiliation

Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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.
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
Department of Orthopedics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
Clinical Research Centre, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

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.

中文翻译：

评估二甲双胍目标对骨关节炎风险的影响：孟德尔随机研究

客观的

使用两个二甲双胍靶标，即 AMP 激活蛋白激酶 (AMPK) 和生长分化因子 15 (GDF-15) 作为二甲双胍替代物，提供有关二甲双胍对骨关节炎 (OA) 影响的一些因果证据。

方法

这是 2 样本孟德尔随机化设计。我们构建了 44 个在 HbA1c (%) 中基因预测的 AMPK 相关变体作为 AMPK 的工具，以及 5 个强烈预测 GDF-15 的变体作为 GDF-15 的工具。三种 OA 表型（包括任何位点的 OA、膝关节 OA 和髋关节 OA）的摘要级数据是从英国生物库和 arcOGEN 对 455,211 名欧洲人进行的最大的全基因组荟萃分析中获得的。主要分析采用逆方差加权法进行。进行加权中位数和 MR-Egger 作为敏感性分析，以评估我们结果的稳健性。

结果

基因预测的 AMPK 与任何部位的 OA 呈负相关（OR：0.60；95% CI：0.43–0.83）和髋部 OA（OR：0.42；95% CI：0.22–0.80），但与膝部 OA 无关（OR：0.85）；95% CI：0.49–1.50）。基因预测的 GDF-15 水平较高可降低髋部 OA 的风险（OR：0.95；95% CI：0.90–0.99），但不会降低任何部位的 OA（OR：1.00；95% CI：0.98–1.02）和膝部 OA （OR：1.02；95% CI：0.98–1.07）。