Impact of the Thr789Ala Variant of the von Willebrand Factor Levels, on Ristocetin Co-Factor and Collagen Binding Capacity and its Association with Coronary Heart Disease in Patients With Diabetes Mellitus Type 2

Abstract

A Thr789Ala variant in the von Willebrand Factor (vWF) gene is associated with increased vWF plasma concentrations and might therefore affect the risk of coronary heart disease (CHD) in the general population. Patients with type 2 diabetes have an increased risk for premature atherosclerosis and are characterized by alterations of the coagulation system. However, it is not known whether the Thr789Ala variant in the vWF gene contributes to the increased CHD risk in patients with type 2 diabetes. We therefore investigated the potential relationship between the Thr789Ala variant in the vWF gene and the occurrence of CHD in 356 patients with type 2 diabetes, either with (DM+/CHD+, n = 204) or without evidence for CHD (DM+/CHD-, n = 152). In addition, two control groups without type 2 diabetes, with (DM-/CHD+, n = 22) or without CHD (DM-/CHD-, n = 100), were investigated. Individuals with the vWF Thr789Ala variant have significantly higher von Willebrand factor plasma concentrations (p < 0.001). In addition, ristocetin co-factor was significantly increased in vWF Thr789Ala variant carriers (p < 0.05). Ristocetin co-factor levels and collagen binding capacity were also increased in individuals affected with either type 2 diabetes, CHD or both (DM+/CHD+, DM+/CHD-, DM-/CHD+) as compared to healthy controls (DM-/CHD-) (p < 0.001). However, we did not find an association between the vWF Thr789Ala variant and the occurrence of CHD in patient with type 2 diabetes (p = 0.34). In conclusion, although the Thr789Ala vWF gene variant is associated with increased plasma concentrations of vWF, ristocetin co factor levels and collagen binding capacity in patients with type 2 diabetes and CHD, a direct effect of this variant on the occurrence of CHD in patients with type 2 diabetes, could not be detected.

Key words

vWF - type 2 diabetes - CHD - Thr789Ala variant

References

• 1 Ballard D J, Humphrey L L, Melton 3rd L J. Epidemiology of persistent proteinuria in typ II diabetes mellitus. Population based study in Rochester Minnesota.  Diabetes. 1998;  37 405-412
• 2 Blüher M, Unger R, Rassoul F, Richter V, Paschke R. Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes.  Diabetologia. 2002;  45 210-216
• 3 Caprio S, Wong S, Alberti K GMM. Cardiovascular complications of diabetes.  Diabetologia. 1997;  40 B78-B82
• 4 Carr M E. Diabetes mellitus A hypercoagulable state.  Journal of Diabetes and its Complications. 2001;  15 44-45
• 5 Diabetes Control and Complication Trial Research Group . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med. 1993;  329 977-983
• 6 The Expert Committee on the Diagnosis and Classification of Diabetes mellitus . Report the Expert Committee on the Diagnosis and Classification of Diabetes mellitus (Committee Report).  Diabetes Care. 1998;  21 (Suppl 1) S5-S19
• 7 Haffner S M, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality form coronary heart disease in subjacts with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.  N Engl J Med. 1998;  339 229-234
• 8 Hopfner R L, Gopalakrishnan V. Endothelin: emerging role in diabetic vascular Complications.  Diabetologia. 1999;  42 1383-1394
• 9 Jager A, van Hinsbergh V W, Kostense P J, Emeis J J, Yudkin J S, Nijpels G, Dekker J M, Heine R J, Bouter L M, Stehouwer C D. Von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study.  Arterioscler Thromb Vasc Biol. 1999;  19 3071-3078
• 10 Jansson J H, Nilsson T K, Johnson O. A novel risk factor for recurrent myocardial infarction and death.  British Heart Journal. 1991;  66 351-355
• 11 Kunkel G R, Graham J B, Fowlkes D M, Lord S T. Rsa I polymorphism in von Willebrand factor (vWF) at codon 789.  Nucl Acids Res. 1990;  18 7467
• 12 Lacquemant C, Gaucher C, Delorme C, Chatellier G, Gallois Y, Rodier M, Passa P, Balkau B, Mazurier C, Marre M, Froguel P. For the GENEDIAB Study Group, and the DESIR Study Group: Association between high von Willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type 1 diabetes.  Kidney Int. 2000;  57 1437-1443
• 13 Leurs P B, Stolk R P, Hamulyak K, Van Oerle R, Grobbee D E, Wolffenbuttel B H. Tissue factor pathway inhibitor and other endothelium-dependent hemostatic factors in elderly individuals with normal or impaired glucose tolerance and type 2 diabetes.  Diabetes Care. 2002;  25 1340-1345
• 14 Lip G, Blann A. Von Willebrand factor: a marker of endothelial dysfunction in vascular disorders?.  Cardiovasc Res. 1997;  34 255-265
• 15 Panzram G. Mortality and survival in Type 2 (non insulin dependent) diabetes mellitus.  Diabetologia. 1987;  30 123-131
• 16 Pettitt D J, Saad M F, Bennett P H, Nelson R G, Knowler W C. Familial predisposition to renal disease in two generations of Pima indians with type II (non-insulin dependent) diabetes mellitus.  Diabetologia. 1990;  33 438-443
• 17 Rossing P, Rossing K, Jacobsen P. Unchanged incidence of diabetic nephropathy in IDDM patients.  Diabetes. 1995;  44 739-743
• 18 Schiekofer S, Balletshofer B, Andrassy M, Bierhaus A, Nawroth P P. Endothelial dysfunction in diabetes mellitus.  Semin Thromb Hemost. 2000;  26 503-511
• 19 Seaquist E R, Goetz F C, Rich S, Barbosa J. Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy.  New Engl J Med. 1989;  320 1161-1165
• 20 Standl E, Balletshofer B, Dahl B, Weichenhain B, Stiegler H, Hörmann A, Holle R. Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich General Practitioner Project.  Diabetologia. 1996;  39 1540-1545
• 21 Takahashi H, Ito S, Hanano M, Wada K, Niwano H, Seki Y, Shibata A. Circulating thrombomodulin as a novel endothelial cell marker: comparison of its behavior with von Willebrand factor and tissue-type plasminogen activator.  Am J Hematol. 1992;  42 32-39
• 22 Thompson S G, Kienast J, Pyke S DM, Haverkate F, van de Loo J CW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  N Engl J Med. 1995;  332 635-641