Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study
Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study
复制标题
DOI：
10.1016/j.joca.2022.06.010
复制
发表时间：
2022-10-15
影响因子：
7
通讯作者：
Ding，C.
中科院分区：
文献类型：
--
作者：
Zhang，Y.;Li，D.;Ding，C.
目的利用二甲双胍的两个靶点，即amp活化蛋白激酶（AMPK）和生长分化因子15 （GDF-15）作为二甲双胍的替代指标，为二甲双胍对骨关节炎（OA）的影响提供一些因果证据。方法采用双样本孟德尔随机化设计。我们构建了44个AMPK相关变异作为HbA1c基因预测AMPK的工具（%），5个变异作为GDF-15的工具强烈预测GDF-15。从英国生物银行和arcOGEN的455,211名欧洲人的最大全基因组荟萃分析中获得了三种OA表型的汇总数据，包括任何部位的OA，膝关节OA和髋关节OA。主要分析采用反方差加权法。加权中位数和MR-Egger进行敏感性分析，以评估我们结果的稳健性。结果遗传预测AMPK与任何部位的OA （OR: 0.60; 95% CI: 0.43-0.83）和髋关节OA （OR: 0.42; 95% CI: 0.22-0.80）呈负相关，但与膝关节OA无关（OR: 0.85; 95% CI: 0.49-1.50）。较高水平的基因预测GDF-15降低了髋部OA的风险（OR: 0.95; 95% CI: 0.90-0.99），但没有降低任何部位OA （OR: 1.00; 95% CI: 0.98-1.02）和膝关节OA （OR: 1.02; 95% CI: 0.98-1.07）。结论AMPK和GDF-15可能是骨性关节炎的潜在治疗靶点，尤其是髋部骨性关节炎，二甲双胍可能被重新用于骨性关节炎的治疗，这需要在随机对照试验中得到验证。
ObjectiveTo 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.MethodsThis 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.ResultsGenetically 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).ConclusionThis 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.