BACKGROUND AND PURPOSE We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of genetically proxied AMP-activated protein kinase (AMPK) activation, which is the target of metformin, on functional outcome following ischemic stroke onset. METHODS A total of 44 AMPK-related variants associated with HbA1c (%) were used as instruments for AMPK activation. The primary outcome was the modified Rankin Scale (mRS) score at 3 months following the onset of ischemic stroke, evaluated as a dichotomous variable (3-6 vs. 0-2) and subsequently as an ordinal variable. Summary-level data for the 3-month mRS were obtained from the Genetics of Ischemic Stroke Functional Outcome network, including 6,165 patients with ischemic stroke. The inverse-variance weighted method was used to obtain causal estimates. The alternative MR methods were used for sensitivity analysis. RESULTS Genetically predicted AMPK activation was significantly associated with lower odds of poor functional outcome (mRS 3-6 vs. 0-2, odds ratio [OR]: 0.06, 95% confidence interval [CI]: 0.01-0.49, P=0.009). This association was maintained when 3-month mRS was analyzed as an ordinal variable. Similar results were observed in the sensitivity analyses, and there was no evidence of pleiotropy. CONCLUSION This MR study provided evidence that AMPK activation by metformin may exert beneficial effects on functional outcome following ischemic stroke.

中文翻译：

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遗传代理 AMPK 激活（二甲双胍的靶标）对缺血性中风后功能结果的影响。

背景和目的 我们进行了双样本孟德尔随机化 (MR) 分析，以评估遗传代理 AMP 活化蛋白激酶 (AMPK) 激活（二甲双胍的靶标）对缺血性卒中发作后功能结果的因果影响。方法 总共使用 44 种与 HbA1c (%) 相关的 AMPK 相关变体作为 AMPK 激活的工具。主要结果是缺血性卒中发作后 3 个月的改良 Rankin 量表 (mRS) 评分，作为二分变量（3-6 与 0-2）进行评估，随后作为序数变量进行评估。3 个月 mRS 的汇总数据来自缺血性卒中功能结果遗传学网络，包括 6,165 名缺血性卒中患者。逆方差加权法用于获得因果估计。替代 MR 方法用于敏感性分析。结果 遗传预测的 AMPK 激活与较低的不良功能结果几率显着相关（mRS 3-6 与 0-2，优势比 [OR]：0.06，95% 置信区间 [CI]：0.01-0.49，P=0.009） . 当将 3 个月的 mRS 作为有序变量进行分析时，这种关联得以维持。在敏感性分析中观察到类似的结果，并且没有多效性的证据。结论 这项 MR 研究提供的证据表明，二甲双胍激活 AMPK 可能对缺血性卒中后的功能结果产生有益影响。P=0.009）。当将 3 个月的 mRS 作为有序变量进行分析时，这种关联得以维持。在敏感性分析中观察到类似的结果，并且没有多效性的证据。结论 这项 MR 研究提供的证据表明，二甲双胍激活 AMPK 可能对缺血性卒中后的功能结果产生有益影响。P=0.009）。当将 3 个月的 mRS 作为有序变量进行分析时，这种关联得以维持。在敏感性分析中观察到类似的结果，并且没有多效性的证据。结论 这项 MR 研究提供的证据表明，二甲双胍激活 AMPK 可能对缺血性卒中后的功能结果产生有益影响。