Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
Diabetes Care. 2020 Apr;43(4):835-842. doi: 10.2337/dc19-1973. Epub 2020 Feb 4.
To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach.
A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo ( = 31,200).
Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89-0.95]; = 1.79 × 10). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; = 8.73 × 10). After standardization, the GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07-0.51] vs. 0.76 [0.60-0.97], respectively; = 0.007 for difference).
These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice.
采用孟德尔随机化（MR）方法，确定血管紧张素转换酶抑制剂（ACEI）是否降低 2 型糖尿病的发病风险。
本两样本 MR 分析纳入了 ORIGIN 临床试验（注册号 NCT00069784）中 4147 名参与者的 17 个与 ACE 血清浓度相关的独立遗传变异，以及 DIAbetes Genetics Replication And Meta-analysis（DIAGRAM）联盟 18 项研究中 ACEI 对 2 型糖尿病风险的影响。然后，我们在包括 UK Biobank 中 341872 名参与者（其中 16320 名患有 2 型糖尿病）的研究中，对反映 ACE 浓度降低的遗传风险评分（GRS）与 2 型糖尿病患病率进行了关联分析。然后，我们将标准化后的血压变化的 MR 估计值与 ACEI 与安慰剂的随机对照试验（RCT）荟萃分析（ = 31200）获得的估计值进行了比较。
遗传上 ACE 浓度较低与 2 型糖尿病发病风险降低相关（每标准差 OR 0.92 [95%CI 0.89-0.95]； = 1.79×10）。该结果在 UK Biobank 中得到了验证（每标准差 OR 0.97 [0.96-0.99]； = 8.73×10）。标准化后，GRS 与每降低 2.4mmHg 平均动脉压（MAP）导致的 2 型糖尿病风险降低幅度相关，与 RCT 荟萃分析获得的结果相比更大（每降低 2.4mmHg MAP 的 OR 0.19 [0.07-0.51] 与 0.76 [0.60-0.97]，分别； = 0.007 用于差异检验）。
这些结果支持 ACEI 对 2 型糖尿病发病风险的保护作用，可能为临床实践中的治疗决策提供指导。
