Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM

Abstract

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

Angiotensin‐converting enzyme gene and diabetes mellitus

“…These findings are in keeping with earlier work in which the frequency of the I allele was significantly lower in those with albuminuria, suggesting that possession of the I allele may be protective[52]. There have, however, been several studies in which no association was found between ACE genotype and nephropathy[53–56].…”

Association of angiotensin‐converting enzyme DD genotype with 24‐h blood pressure abnormalities in normoalbuminuric children and adolescents with Type 1 diabetes

“…Results of the distribution of the ACE genotypes in previous studies on adult populations are conflicting [7,16,21,30–32]. Some studies described a higher prevalence of the DD genotype in younger than in older people [2,33] and others found this genotype to be associated with human longevity [34].…”

Genetic determinants of diabetic nephropathy

“…This polymorphism has also been examined in diabetic nephropathy, again with conflicting results. In our own much larger study [49], and others [57], no such association was found, although one study has suggested an association of the TT genotype with elevated blood pressure in patients with nephropathy [58]. In our own much larger study [49], and others [57], no such association was found, although one study has suggested an association of the TT genotype with elevated blood pressure in patients with nephropathy [58].…”

“…Thus the II genotype is associated with low levels of serum ACE, whereas the DD genotype is associated with high levels, with ID genotypes having intermediate levels of ACE. However, our own and other subsequent large studies examining over 1000 patients with and without nephropathy have shown no association between nephropathy and the D allele [47][48][49]. In diabetic nephropathy two small studies have suggested an association between the D allele of the ACE gene and nephropathy [45,46].…”