Contribution of gene polymorphisms in the renin-angiotensin system to macroangiopathy in patients with diabetic nephropathy.

The renin-angiotensin system is important in the control of hemodynamic status and pathogenesis of macrovascular disease, which is a major cause of morbidity and mortality in patients with type 2 diabetes with nephropathy. Serum angiotensin-converting enzyme (ACE) and angiotensinogen (Atg) levels are related to their respective gene polymorphisms. Seventy patients with type 2 diabetes with overt nephropathy (serum creatinine >/= 1.5 mg/dL) were studied. Serum ACE activity was measured by the spectrophotometric method. ACE deletion/insertion (D/I) and Atg M235T genotypes were determined by polymerase chain reaction. Patients with and without macroangiopathy were compared. Those with macroangiopathy had increased ACE activity (median, 60.9 U/L; range, 37.9 to 100 U/L versus without macroangiopathy, 47.9 U/L; range, 11.2 to 84.5 U/L; P = 0.01) and prevalence of ACE DD/DI genotypes (DD/DI:II: with macroangiopathy, 61%:39% versus without macroangiopathy, 34%:66%; P = 0.03). Multivariate analysis using age; sex; duration of diabetes; glycemic, blood pressure, and lipid level control; serum creatinine level; and presence of the ACE D allele showed that presence of the D allele (P = 0.03; odds ratio, 1.8; confidence interval, 1.1 to 3.1) and serum creatinine level (P = 0.0007) were independent risk factors for macroangiopathy. Association of the D allele became insignificant after serum ACE activity was included in the analysis in which only serum ACE activity (P = 0.004) and serum creatinine level (P = 0.01) were independent risk factors. Neither Atg M235T nor its synergistic effect with the ACE D allele showed an association with macroangiopathy. In conclusion, the ACE D allele is associated with macroangiopathy in Chinese patients with type 2 diabetes with nephropathy. The association is dependent on its effect on serum ACE activity, which is an independent risk factor for the development of macroangiopathy.