Association between high von willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type I diabetes. The GENEDIAB Study Group and the DESIR Study Group.
BACKGROUND
A genetic susceptibility for diabetic kidney disease is suspected since diabetic nephropathy occurs in only 30 to 40% of type I diabetic patients. As elevated von Willebrand factor (vWF) plasma concentrations have been reported to precede the development of microalbuminuria in type I diabetes, we addressed a possible implication of vWF as a genetic determinant for diabetic nephropathy.


METHODS
Three known vWF gene polymorphisms were genotyped in a group of 493 type I diabetic subjects, all showing proliferative retinopathy, but with various stages of renal involvement, which ranged from no microalbuminuria, despite a mean duration of diabetes of 31 years, to advanced nephropathy (GENEDIAB Study): Thr789Ala (Rsa I), M-/M+ (Msp I) (intron 19), and Ala1381Thr (Hph I). Plasma vWF and factor VIII (F VIII) levels were also measured in this population.


RESULTS
Plasma vWF and F VIII levels were increased in diabetic subjects with nephropathy (P < 0.001) or with coronary heart disease (CHD; P < 0.001), but there was no interaction of both conditions on plasma levels. The Msp I polymorphism (M-/M+) was weakly associated with nephropathy (P = 0. 04), but this association was not more significant when other risk factors were used in a logistic regression analysis. The vWF Thr789Ala polymorphism was associated with CHD (P = 0.002) and with plasma vWF levels. Logistic regression analysis indicated an independent and codominant effect of the Thr789Ala polymorphism on CHD, but not on nephropathy, with a maximal risk for Ala/Ala homozygotes (OR = 4.2, 95% CI, 1.8 to 9.9, P = 0.0008).


CONCLUSIONS
It is unlikely that polymorphisms in the vWF gene contribute to the risk for nephropathy in type I diabetic patients. However, the Thr789Ala polymorphism might affect the risk for CHD in this population through modulation of plasma vWF levels.
Lacquemant
C
C
Laboratoire de Génétique des Maladies Multifactorielles, CNRS UPRES A 8090, Institut de Biologie de Lille, and Laboratoire Français du Fractionnement et des Biotechnologies, Lille; Arras Hospital; Medical Informatics, Broussais Hospi.
Gaucher
C
C
Delorme
C
C
Chatellier
G
G
Gallois
Y
Y
Rodier
M
M
Passa
P
P
Balkau
B
B
Mazurier
C
C
Marre
M
M
Froguel
P
P
D000293:Adolescent; D000328:Adult; D002648:Child; D003327:Coronary Disease / Q000097:blood / Q000235:genetics; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000097:blood; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics; D005169:Factor VIII / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D011110:Polymorphism, Genetic / Q000235:genetics*; D012016:Reference Values; D014841:von Willebrand Factor / Q000032:analysis* / Q000235:genetics*
D014841:von Willebrand Factor; D005169:Factor VIII