Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in tile USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, <1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 ± 0.86 mg/dl), ACE genotype frequencies were 11:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silencer motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, thse results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/ polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.