ACE and Type 2 Diabetes Risk: A Mendelian Randomization Study

Marie Pigeyre; Jennifer Sjaarda; Michael Chong; Sibylle Hess; Jackie Bosch; Salim Yusuf; Hertzel Gerstein; Guillaume Paré

doi:10.2337/dc19-1973

Pathophysiology/Complications

ACE and Type 2 Diabetes Risk: A Mendelian Randomization Study

Marie Pigeyre¹,²,³,
Jennifer Sjaarda¹,²,⁴,
Michael Chong¹,²,⁴,
Sibylle Hess⁵,
Jackie Bosch¹,⁶,
Salim Yusuf¹,⁷,
Hertzel Gerstein¹,³ and
Guillaume Paré¹,²,⁴,⁷ ⇑

¹Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
²Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
³Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
⁴Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
⁵R&D, Translational Medicine & Early Development, Biomarkers & Clinical Bioanalyses, Sanofi Aventis Deutschland GmbH, Frankfurt, Germany
⁶School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
⁷Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

Corresponding author: Guillaume Paré, pareg{at}mcmaster.ca

Diabetes Care 2020 Apr; 43(4): 835-842. https://doi.org/10.2337/dc19-1973

Abstract

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) (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 (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.

Footnotes

This article contains Supplementary Data online at https://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-1973/-/DC1.

Received October 4, 2019.
Accepted January 7, 2020.

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