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 sta tus and pathogenesis of macrovascular disease, which is a major cause of mo rbidity and mortality in patients with type 2 diabetes with nephropathy, Se rum angiotensin-converting enzyme (ACE) and angiotensinogen (Atg) levels ar e related to their respective gene polymorphisms. Seventy patients with typ e 2 diabetes with overt nephropathy (serum creatinine greater than or equal to 1.5 mg/dL) were studied. Serum ACE activity was measured by the spectro photometric method. ACE deletion/insertion (D/I) and Atg M235T genotypes we re determined by polymerase chain reaction. Patients with and without macro angiopathy were compared. Those with macroangiopathy had increased ACE acti vity (median, 60.9 U/L; range, 37.9 to 100 U/L versus without macroangiopat hy, 47.9 U/L; range, 11.2 to 84.5 U/L; P = 0.01) and prevalence of ACE DD/D I genotypes (DD/DI:II: with macroangiopathy, 61%:39% versus without macroan giopathy, 34%:66%; P = 0.03), Multivariate analysis using age; sex; duratio n of diabetes; glycemic, blood pressure, and lipid level control; serum cre atinine 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 macro angiopathy, Association of the D allele became Insignificant after serum AC E 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 facto rs. Neither Atg M235T nor its synergistic effect with the ACE D allele show ed an association with macroangiopathy, In conclusion, the ACE D allele is associated with macroangiopathy in Chinese patients with type 2 diabetes wi th nephropathy. The association is dependent on its effect on serum ACE act ivity, which is an independent risk factor for the development of macroangi opathy, (C) 2001 by the National Kidney Foundation, Inc.