OBJECTIVE To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS 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; 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 (n = 31,200). RESULTS 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]; P = 1.79 × 10-7). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; P = 8.73 × 10-4). After standardization, the ACE 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; P = 0.007 for difference). CONCLUSIONS These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice.

中文翻译：

---

ACE和2型糖尿病风险：孟德尔随机研究。

目的使用孟德尔随机（MR）方法确定ACE抑制剂是否可降低2型糖尿病的风险。研究设计与方法一项包括两个样本的MR分析，包括来自初始甘精胰岛素干预后的结果减少（ORIGIN； NCT00069784）试验的4147名参与者中的17种与ACE血清浓度相关的独立遗传变异，其对2型糖尿病风险的影响从18糖尿病遗传学复制和荟萃分析（DIAGRAM）联盟的研究。然后，来自UK Biobank的341,872名参与者（其中16,320名患有2型糖尿病）参加了测试，以支持较低ACE浓度的遗传风险评分（GRS）与2型糖尿病患病率的关联。在标准化血压变化后比较MR估算值，从ACE抑制剂和安慰剂的随机对照试验（RCT）荟萃分析获得的估计值（n = 31,200）。结果从基因上讲，较低的ACE浓度与较低的2型糖尿病风险相关（按SD 0.92 [95％CI 0.89-0.95]的赔率[OR]； P = 1.79×10-7）。该结果在英国生物库中得到了重复（或根据SD 0.97 [0.96-0.99]； P = 8.73×10-4）。标准化后，与通过RCT荟萃分析获得的ACE GRS相比，每降低2.4 mmHg的平均动脉压（MAP）降低的2型糖尿病风险（每降低2.4 mmHg的MAP降低0.19 [0.07-分别为0.51和0.76 [0.60-0.97]；差异为P = 0.007）。