Angiotensin converting enzyme gene polymorphism: Potential silencer motif and impact on progression in IgA nephropathy

Abstract

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 the 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 II: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 silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these 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/D 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.

Preventing end stage renal disease in diabetic patients — genetic aspect (part I)

“…Healthy individuals 84 and patients with diabetic nephropathy 62 carrying the DD genotype were shown to have the highest circulating ACE levels, the II carriers the lowest and ID patients intermediate levels. To gain information about the functional significance of the ACE/ID polymorphism, Hunley et al 85 sequenced the inserted DNA string. Homology between 13 base pairs in the "insert"and a known negative regulator element was interpreted as the possible mechanism of lower ACE generation in the presence of the I allele.…”

Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia

“…48 Amplification using the primers 5Ј-AATGCTTGTAGCCAAAGTCACCT-3Ј and 5Ј-GGCTTTGCTTTGTCTTGTTG-3Ј results in an 856-bp product. 49 Subsequent digestion with DdeI produces two bands of 602-bp and 254-bp for the A allele, with the C allele having two smaller bands (143-bp and 111-bp) in place of the 254-bp band. The PCR reaction mixture was the same as for the ACE I/D polymorphism.…”

Effects of the angiotensinogen gene M235T and A(-6)G variants on blood pressure and other vascular risk factors in a Spanish population

“…The AGT M235T polymorphism was typed by the mismatch method previously described 16,25 with some modifications. Primers used were:…”