Angiotensinogen gene T235 variant: a marker for the development of persistent microalbuminuria in children and adolescents with type 1 diabetes mellitus

Abstract

Aim We examined genetic polymorphisms in the renin–angiotensin system (RAS) coding for angiotensin I-converting enzyme ( ACE) insertion/deletion ( I/D) for angiotensinogen ( AGT) M235T and angiotensin II receptor type 1 ( AGTR1) A1166C as predictors for the development of microalbuminuria (MA) in children with type 1 diabetes mellitus (T1DM). Methods Four hundred fifty-three (215 males, 238 females) T1DM children [median (interquartile range): age, 16.7 years (13.9–18.3); diabetes duration, 6.9 years (3.3–10.8); age at diagnosis, 9.1 years (5.8–11.8)] were followed prospectively from diagnosis until the development of MA (two of three consecutive overnight urine samples with albumin excretion rates of ≥20 and <200 μg/min). Kaplan–Meier survival curves and Cox proportional multivariate model estimated the probability of developing MA and the relative risk for MA among different variables. Results MA developed in 41 (9.1%) subjects. The frequencies of genotypes were as follows: ACE-II 112 (25%), ACE-ID 221 (49%), and ACE-DD 117 (26%) ( n=450); AGT-MM 144 (32%), AGT-MT 231 (51%), and AGT-TT 77 (17%) ( n=452); AGTR1-AA 211 (47%), AGTR1-AC 204 (45%), and AGTR1-CC 37 (8%) ( n=452). The cumulative risk for the development of MA was higher in ACE-DD versus ACE-ID/II groups (log-rank test, P=.05), and a trend was noticed when AGT-TT was compared to AGT-MT/MM groups (log-rank test, P=.08). AGT-TT polymorphism conferred a fourfold increased risk for MA compared to AGT-MM/MT (hazard ratio=3.8; 95% confidence interval=1.43–10.3; P=.008). Interpretation Our findings suggest that RAS gene polymorphism at AGT M235T is a strong predictor for early MA in young T1DM subjects.