Association between angiotensin-converting enzyme gene polymorphisms and diabetic nephropathy: case-control, haplotype, and family-based study in three European populations.
Angiotensin 1-converting enzyme gene (ACE) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients (with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [> or =15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed of 244 trios with DN probands and 288 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C, rs4311-T, Insertion/deletion (I/D or rs1799752)-D, rs4366-G, and rs12449782-G alleles were associated with an increased risk for DN, homogeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366_G and rs12449782_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmission to DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN; these findings were not confirmed in a family-based association study. This study population is suitable to search for additional candidate genes for DN.
Hadjadj
Samy
S
CHU de Poitiers, Department of Diabetology, Poitiers University Hospital, Poitiers, France. s.hadjadj@chu-poitiers.fr
Tarnow
Lise
L
Forsblom
Carol
C
Kazeem
Gbenga
G
Marre
Michel
M
Groop
Per-Henrik
PH
Parving
Hans-Henrik
HH
Cambien
François
F
Tregouet
David A
DA
Gut
Ivo G
IG
Théva
Alexandre
A
Gauguier
Dominique
D
Farrall
Martin
M
Cox
Roger
R
Matsuda
Fumihiko
F
Lathrop
Mark
M
Hager-Vionnet
Nathalie
N
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic
D007703:Peptidyl-Dipeptidase A