ANGIOTENSIN-CONVERTING ENZYME GENE POLYMORPHISM - POTENTIAL SILENCER MOTIF AND IMPACT ON PROGRESSION IN IGA NEPHROPATHY

Since the renin angiotensin system (RAS) is established as an importan t factor in renal disease progression, we determined whether RAS allel es that have been linked to variability in outcome in several cardiova scular diseases also affect progression of IgA nephropathy. These gene tic variants include: (1) angiotensin I converting enzyme deletion pol ymorphism in intron 16 (ACE I/D), reported to be associated with incre ased risk of myocardial infarction as well as left ventricular hypertr ophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), rep orted to be associated with hypertension in Caucasians; and (3) an ang iotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) w hich shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR ampl ification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal st atus was followed for an average of almost seven years. Patients who p resented with and maintained normal serum creatinine (Cr, <1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, i n patients with progression (initially normal Cr increased to a mean o f 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, D D:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The as sociation of the DD genotype with progression was even more striking w hen patients with other risk factors (hypertension and/or heavy protei nuria) were excluded. In this subgroup, the genotype frequencies in pa tients 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, progre ssors vs. non-progressors). Further, sequence analysis of the I gene p olymorphism revealed a potential 13 bp silencer motif. Neither the Agt 235T nor the ATRA 1166C gene variants, however, was associated with d eterioration of renal func tion. Taken together, these results indicat e that, although polymorphism in each of the three genes in the RAS sy stem has been linked to cardiovascular diseases, only the ACE I/D poly morphism is associated with progressive deterioration in renal functio n in IgA nephropathy. Since previous observations link ACE polymorphis m with ACE activity, these findings imply a widespread importance of A CE in modulating destructive processes in different organs.