Angiotensinogen gene T235 variant: a marker for the development of persistent microalbuminuria in children and adolescents with type 1 diabetes mellitus.
OBJECTIVE
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 > or =20 and <200 microg/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).


CONCLUSIONS
Our findings suggest that RAS gene polymorphism at AGT M235T is a strong predictor for early MA in young T1DM subjects.
Gallego
Patricia H
PH
Department of Pediatric Endocrinology and Diabetes, Princess Margaret Hospital, Perth, WA, Australia. patricG4@chw.edu.au
Shephard
Neil
N
Bulsara
Max K
MK
van Bockxmeer
Frank M
FM
Powell
Brenda L
BL
Beilby
John P
JP
Arscott
Gillian
G
Le Page
Michael
M
Palmer
Lyle J
LJ
Davis
Elizabeth A
EA
Jones
Timothy W
TW
Choong
Catherine S Y
CS
D000293:Adolescent; D000419:Albuminuria / Q000235:genetics*; D000808:Angiotensinogen / Q000235:genetics*; D001315:Australia; D002648:Child; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000652:urine*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012084:Renin-Angiotensin System / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044465:White People
D017931:DNA Primers; D005819:Genetic Markers; D000808:Angiotensinogen