ACE I/D Polymorphism, Plasma ACE Levels, and Long-term Kidney Outcomes or All-Cause Death in Patients With Type 1 Diabetes
Research Design and Methods: 1155 participants from 3 French and Belgian cohorts were followed for a median (interquartile range) duration of 14 (13) years. The primary outcome was the occurrence of end-stage kidney disease (ESKD) or a 40% drop in estimated glomerular filtration rate (eGFR). Secondary outcomes were the individual components of the primary outcome, rapid decline in eGFR (steeper than -3 ml/min/1.73m2/year), incident albuminuria, all-cause death, and a composite ESKD or all-cause death. Hazard ratios (HR) 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 increased risk of the primary outcome. 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 ACE I/D polymorphism was associated with increased risk of major kidney events and all-cause death in patients with long-standing type 1 diabetes.