Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK Biobank: a Mendelian randomisation study
Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK Biobank: a Mendelian randomisation study
复制标题
DOI：
10.1007/s00125-020-05243-z
复制
发表时间：
2020-08-04
期刊：
影响因子：
8.2
通讯作者：
Au Yeung, Shiu Lun
中科院分区：
文献类型：
--
作者：
Luo, Shan;Schooling, C. Mary;Au Yeung, Shiu Lun
目的/假设二甲双胍是否降低心血管或癌症风险尚不清楚，因为观察性研究中存在不死时间偏倚和混杂因素。本研究评估了二甲双胍的靶点AMPK对心血管疾病和癌症风险的影响。方法采用孟德尔随机设计，使用二甲双胍的药理学靶点AMPK，在英国生物库中的白色英国血统参与者中推断二甲双胍对心血管疾病和癌症风险的AMPK途径依赖性影响。199名参与者（平均年龄56.9岁; 54.1%为女性），包括26，690例2型糖尿病，38，098例冠状动脉疾病和80，941例整体癌症。通过AMPK变异检测HbA（1c）（%）的遗传预测降低与2型糖尿病风险降低61%相关（OR 0.39; 95% CI 0.20，0.78;p = 7.69 x 10（-3）），冠状动脉疾病风险降低53%（OR 0.47; 95% CI 0.26，0.84;p = 0.01）和总体癌症风险降低44%（OR 0.56; 95% CI 0.36，0.85;p = 7.23 x 10（-3））。使用AMPK评分的中位数或四分位数得出的结果相似，具有剂量反应效应（2型糖尿病的pfor趋势= 4.18 × 10（-3），冠状动脉疾病的pfor趋势= 4.37 × 10（-3），总体癌症的pfor趋势= 4.04 × 10（-3））。结论/解释本研究提供了一些遗传学证据，表明二甲双胍激活AMPK可以预防心血管疾病和癌症，这需要通过随机对照试验来证实。
Aims/hypothesis Whether metformin reduces cardiovascular or cancer risk is unclear owing to concerns over immortal time bias and confounding in observational studies. This study evaluated the effect of AMP-activated protein kinase (AMPK), the target of metformin, on risk of cardiovascular disease and cancer.Methods This is a Mendelian randomisation design, using AMPK, the pharmacological target of metformin, to infer the AMPK pathway-dependent effects of metformin on risk of cardiovascular disease and cancer in participants of white British ancestry in the UK Biobank.Results A total of 391,199 participants were included (mean age 56.9 years; 54.1% women), including 26,690 cases of type 2 diabetes, 38,098 cases of coronary artery disease and 80,941 cases of overall cancer. Genetically predicted reduction in HbA(1c)(%) instrumented by AMPK variants was associated with a 61% reduction in risk of type 2 diabetes (OR 0.39; 95% CI 0.20, 0.78;p = 7.69 x 10(-3)), a 53% decrease in the risk of coronary artery disease (OR 0.47; 95% CI 0.26, 0.84;p = 0.01) and a 44% decrease in the risk of overall cancer (OR 0.56; 95% CI 0.36, 0.85;p = 7.23 x 10(-3)). Results were similar using median or quartiles of AMPK score, with dose-response effects (pfor trend = 4.18 x 10(-3)for type 2 diabetes, 4.37 x 10(-3)for coronary artery disease and 4.04 x 10(-3)for overall cancer).Conclusions/interpretation This study provides some genetic evidence that AMPK activation by metformin may protect against cardiovascular disease and cancer, which needs to be confirmed by randomised controlled trials.