Genetic variability of von Willebrand factor and risk of coronary heart disease: the Rotterdam Study

The von Willebrand factor (VWF) may be causally associated with coronary heart disease (CHD) or merely be a marker of endothelial damage. The G allele of the −1793 C/G promoter polymorphism in the VWF gene has been associated with higher plasma levels of VWF. To investigate whether VWF has a causal role in CHD, we designed a case‐cohort study, including 352 subjects with CHD and a random cohort (n = 736), and prospectively examined the association of the −1793 C/G polymorphism with CHD in subjects with and without advanced atherosclerosis. All subjects were ≤75 years of age and participating in the population‐based Rotterdam Study. Atherosclerosis was assessed by the ankle–arm index. Among subjects with advanced atherosclerosis, heterozygous and homozygous carriers of the G allele had a 3·5 (1·2–10·2) and 1·5 (0·4–5·7) fold increased risk of CHD respectively, compared with C/C homozygotes. The hazard ratio was 2·6 (1·0–6·8) for carriers of at least one copy of the G allele versus non‐carriers. No associations were found in the absence of advanced atherosclerosis. In conclusion, this study suggests that the G allele of the −1793 C/G polymorphism in the VWF gene is associated with an increased risk of CHD, but only in subjects with advanced atherosclerosis.

[1]  A. Hofman,et al.  Determinants of disease and disability in the elderly: The Rotterdam elderly study , 1991, European Journal of Epidemiology.

[2]  J. Danesh,et al.  von Willebrand factor and coronary heart disease: prospective study and meta-analysis. , 2002, European heart journal.

[3]  J. Vermylen,et al.  atherosclerosis-prone sites in response to hypercholesterolemia Endothelial von Willebrand factor recruits platelets to , 2013 .

[4]  N. Samani,et al.  The −1185 A/G and −1051 G/A dimorphisms in the von Willebrand factor gene promoter and risk of myocardial infarction , 2001, British journal of haematology.

[5]  D. Wagner,et al.  Localized reduction of atherosclerosis in von Willebrand factor-deficient mice. , 2001, Blood.

[6]  R. Medcalf,et al.  Human Endothelial Cell-derived Nuclear Proteins that Recognise Polymorphic DNA Elements in the von Willebrand Factor Gene Promoter Include YY1 , 2001, Thrombosis and Haemostasis.

[7]  T. Spector,et al.  The genetics of haemostasis: a twin study , 2001, The Lancet.

[8]  A. Folsom,et al.  Nontraditional Risk Factors for Coronary Heart Disease Incidence among Persons with Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study , 2000, Annals of Internal Medicine.

[9]  P. Harvey,et al.  A single nucleotide polymorphism at nucleotide −1793 in the von Willebrand factor (VWF) regulatory region is associated with plasma VWF:Ag levels , 2000, British journal of haematology.

[10]  L. Almasy,et al.  Genetic determinants of hemostasis phenotypes in Spanish families. , 2000, Circulation.

[11]  Z. Ruggeri.  Old concepts and new developments in the study of platelet aggregation. , 2000, The Journal of clinical investigation.

[12]  W E Barlow,et al.  Analysis of case-cohort designs. , 1999, Journal of clinical epidemiology.

[13]  L. Bouter,et al.  von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[14]  D. Lillicrap,et al.  Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF :Ag levels : Identification of three novel single nucleotide polymorphisms in the vWF gene promoter , 1999 .

[15]  G. Lowe,et al.  Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study , 1999, British journal of haematology.

[16]  D. Lillicrap,et al.  Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: identification of three novel single nucleotide polymorphisms in the vWF gene promoter. , 1999, Blood.

[17]  L. Weinehall,et al.  High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. , 1998, Circulation.

[18]  T. Nilsson,et al.  von Willebrand factor, tissue plasminogen activator, and dehydroepiandrosterone sulphate predict cardiovascular death in a 10 year follow up of survivors of acute myocardial infarction , 1998, Heart.

[19]  Arno W. Hoes,et al.  Peripheral arterial disease in the elderly: The Rotterdam Study. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[20]  A. Rumley,et al.  Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[21]  A. Folsom,et al.  Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. , 1997, Circulation.

[22]  G. Lip,et al.  von Willebrand factor and its relevance to cardiovascular disorders. , 1995, British heart journal.

[23]  S. Thompson,et al.  Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. , 1995, The New England journal of medicine.

[24]  W. Barlow,et al.  Robust variance estimation for the case-cohort design. , 1994, Biometrics.

[25]  M. Blombäck,et al.  Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. , 1994, Genomics.

[26]  D. Bellinger,et al.  von Willebrand factor and animal models: contributions to gene therapy, thrombotic thrombocytopenic purpura, and coronary artery thrombosis. , 1991, Mayo Clinic proceedings.

[27]  R. Prescott,et al.  Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. , 1991, International journal of epidemiology.

[28]  V. Fuster,et al.  Spontaneous and Diet‐Induced Coronary Atherosclerosis in Normal Swine and Swine with von Wiiiebrand Disease , 1985, Arteriosclerosis.