CONTRIBUTION OF GENETIC-POLYMORPHISM IN THE RENIN-ANGIOTENSIN SYSTEM TO THE DEVELOPMENT OF RENAL COMPLICATIONS IN INSULIN-DEPENDENT DIABETES

Diabetic nephropathy is a glomerular disease due to uncontrolled diabe tes and genetic factors, It can be caused by glomerular hypertension p roduced by capillary vasodilation, due to diabetes, against constituti onal glomerular resistance. As angiotensin II increases glomerular pre ssure, we studied the relationship between genetic polymorphisms in th e renin-angiotensin system-angiotensin I converting enzyme (ACE), angi otensinogen (AGT), and angiotensin II, subtype 1, receptor-and the ren al involvement of insulin-dependent diabetic subjects with proliferati ve retinopathy: those exposed to the risk of nephropathy due to diabet es. Of 494 subjects recruited in 17 centers in France and Belgium (GEN EDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (micro albuminuria), 126 (25%) established (proteinuria), and 107 (22%) advan ced (plasma creatinine greater than or equal to 150 mu mol/liter or re nal replacement therapy) nephropathy, The severity of renal involvemen t was associated with ACE insertion/deletion (IID) polymorphism: chi(2 ) for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052), Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AG T MM to TT genotypes. Thus, genetic determinants that affect renal ang iotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic pati ents.