Prognostic value of angiotensin-1 converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: A prospective study

Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its ins ertion/deletion (I/D) polymorphism, which determines most of ACE interindiv idual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact w ith ACE I/D polymorphism for the risk of diabetic nephropathy, but their pr ognostic values have to be established by follow-up studies. A total of 310 type I diabetes mellitus patients who attended the diabetic clinic in Ange rs (France) took part in a prospective, observational, follow-up study. Gly cohemoglobin, BP, plasma creatinine, and urinary albumin excretion were det ermined periodically. Nephropathy was classified as absent, incipient (micr oalbuminuria), established (proteinuria), advanced (plasma creatinine great er than or equal to 150 mu mol/L), and terminal (renal replacement therapy) . The main end point was the occurrence of a renal event defined as the pro gression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) ha d established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the pati ents. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occ urrence of renal events was significantly influenced by ACE genotype (log-r ank II versus ID versus DD, P < 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confiden ce interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, basel ine plasma ACE concentration was higher in patients who progressed to micro albuminuria (571 +/- 231 versus 466 +/- 181 <mu>g/L; P = 0.0032); the D all ele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributo rs were male gender, baseline systolic BP, and urinary albumin excretion. T he AGT M235T polymorphism was not associated with renal events. The D allel e of the ACE VD polymorphism is an independent risk factor for both the ons et and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.