ACE I/D Polymorphism, Plasma ACE Levels, and Long-term Kidney Outcomes or All-Cause Death in Patients With Type 1 Diabetes

Abstract

OBJECTIVE The deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism is a risk factor for diabetic kidney disease. We assessed its contribution to long-term kidney outcomes and all-cause death in patients with long-standing type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 1,155 participants from three French and Belgian cohorts were monitored for a median duration of 14 (interquartile range 13) years. The primary outcome was the occurrence of end-stage kidney disease (ESKD) or a 40% drop in the estimated glomerular filtration rate (eGFR). Secondary outcomes were the individual components of the primary outcome, rapid decline in eGFR (steeper than –3 mL/min/1.73 m2 per year), incident albuminuria, all-cause death, and a composite ESKD or all-cause death. Hazard ratios (HRs) for XD versus II genotype and for baseline plasma ACE levels were computed by Cox analysis. Genotype performance in stratifying the primary outcome was tested. RESULTS Genotype distribution was 954 XD and 201 II. The primary outcome occurred in 20% of XD and 13% of II carriers: adjusted HR 2.07 (95% CI 1.32–3.40; P = 0.001). Significant associations were also observed for rapid decline in eGFR, incident albuminuria, ESKD, all-cause death, and ESKD or all-cause death. Baseline plasma ACE levels were higher in XD carriers and significantly associated with an increased risk of the primary outcome. The ACE genotype enhanced net reclassification improvement (0.154, 95% CI 0.007–0.279; P = 0.04) and integrated discrimination improvement (0.012, 95%CI 0.001–0.021; P = 0.02) for primary outcome stratification. CONCLUSIONS The D-allele of the ACE I/D polymorphism was associated with an increased risk of major kidney events and all-cause death in patients with long-standing type 1 diabetes.