Association between high von Willebrand factor levels and the Thr789Ala VWF gene polymorphism but not with nephropathy in type 1 diabetes

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 Map 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 Ths789Ala 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). Conclusion. It is unlikely that polymorphisms in the VWF gene contribute to the risk for nephropathy in type I diabetic patients. However, the Thr7898Ala polymorphism might affect the risk for CHD in this population through modulation of plasma VWF levels.