Alpha 2A adrenergic receptor polymorphism is associated with plasma von Willebrand factor levels in a general population

High levels of plasma von Willebrand factor are a proposed risk factor for atherothrombotic disorders. Previously, ABO blood type and the von Willebrand factor −1793C/G polymorphism were shown to affect interindividual variations in plasma von Willebrand factor levels. We previously reported that polymorphisms of the alpha 2A adrenergic receptor, an epinephrine receptor, were associated with platelet function as assessed by platelet function analyzer-100. The measurement value of platelet function analyzer-100 has been reportedly associated with plasma von Willebrand factor levels. Also, it was demonstrated that epinephrine administration increases plasma von Willebrand factor levels in vivo. Thus, the present study investigated the association between plasma von Willebrand factor levels and genetic polymorphisms as follows: ABO blood type, von Willebrand factor −1051G/A (linked with −1793C/G), alpha 2A adrenergic receptor 1780A/G, and alpha 2A adrenergic receptor 2372A/G. Study subjects were genetically unrelated Japanese men (n = 277) recruited at their regular medical examinations. Genotyping of the polymorphisms was performed using the single nucleotide primer extension-based method. Plasma von Willebrand factor levels were measured as ristocetin-cofactor activities. The O blood type and alpha 2A adrenergic receptor 2372AA genotype were significantly associated with lower von Willebrand factor levels, though von Willebrand factor −1051G/A polymorphism did not affect them. In stratification analysis of the group according to blood type O and non-O, the significant association between the 2372AA genotype and lower plasma von Willebrand factor levels was observed in non-O subjects, but not O subjects. In conclusion, the alpha 2A adrenergic receptor 2372A/G polymorphism is associated with plasma von Willebrand factor levels in a general population.

[1]  G. Lippi,et al.  Correlation between von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity and factor VIII activity in plasma , 2008, Journal of Thrombosis and Thrombolysis.

[2]  J. O’Donnell,et al.  ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? , 2006, Transfusion.

[3]  K. Miyaki,et al.  Identification of ADRA2A polymorphisms related to shear-mediated platelet function. , 2006, Biochemical and biophysical research communications.

[4]  U. Vischer,et al.  von Willebrand factor, endothelial dysfunction, and cardiovascular disease , 2006, Journal of thrombosis and haemostasis : JTH.

[5]  S. Liggett,et al.  Complex haplotypes derived from noncoding polymorphisms of the intronless alpha2A-adrenergic gene diversify receptor expression. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Giuseppe Lippi,et al.  Von Willebrand factor and thrombosis , 2006, Annals of Hematology.

[7]  T. Ortel,et al.  Platelet function analyzer (PFA)‐100® closure time in the evaluation of platelet disorders and platelet function , 2006, Journal of thrombosis and haemostasis : JTH.

[8]  J. Nigg,et al.  Association and linkage of α-2A adrenergic receptor gene polymorphisms with childhood ADHD , 2005, Molecular Psychiatry.

[9]  D. Bowen,et al.  An influence of ABO blood group on the rate of proteolysis of von Willebrand factor by ADAMTS13 , 2003, Journal of thrombosis and haemostasis : JTH.

[10]  Z. Ruggeri.  Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation. , 2001, Best practice & research. Clinical haematology.

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

[12]  A. Casellas,et al.  Transgenic mice overexpressing α2A-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasis , 2000, Diabetologia.

[13]  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.

[14]  B. Kobilka,et al.  Two functionally distinct α2-adrenergic receptors regulate sympathetic neurotransmission , 1999, Nature.

[15]  K. Mohlke,et al.  Mvwf, a Dominant Modifier of Murine von Willebrand Factor, Results from Altered Lineage-Specific Expression of a Glycosyltransferase , 1999, Cell.

[16]  H. Vaitkevicius,et al.  Mechanism of epinephrine-induced platelet aggregation. , 1998, Hypertension.

[17]  J. Barrett,et al.  von Willebrand Factor and Factor VIII: C in Acute Cerebrovascular Disease , 1997, Thrombosis and Haemostasis.

[18]  Vischer Um,et al.  Epinephrine induces von Willebrand factor release from cultured endothelial cells: involvement of cyclic AMP-dependent signalling in exocytosis. , 1997 .

[19]  I. Yuasa,et al.  Amplified product length polymorphism (APLP): a novel strategy for genotyping the ABO blood group , 1996, Human Genetics.

[20]  P. Grant,et al.  Levels of von Willebrand Factor, Insulin Resistance Syndrome, and a Common vWF Gene Polymorphism in Non‐insulin‐dependent (Type 2) Diabetes Mellitus , 1996, Diabetic medicine : a journal of the British Diabetic Association.

[21]  M. Chester,et al.  A Rapid and Simple ABO Genotype Screening Method Using a Novel B/O2 versus A/O2 Discriminating Nucleotide Substitution at the ABO Locus , 1995, Vox sanguinis.

[22]  K. Titani,et al.  ABO Blood Group Genotype and Plasma von Willebrand Factor in Normal Individuals , 1995, Vox sanguinis.

[23]  C. Samama,et al.  Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  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.

[25]  K. Titani,et al.  Human plasma alpha 2-macroglobulin and von Willebrand factor possess covalently linked ABO(H) blood group antigens in subjects with corresponding ABO phenotype. , 1993, Blood.

[26]  M Lafontan,et al.  Fat cell adrenergic receptors and the control of white and brown fat cell function. , 1993, Journal of lipid research.

[27]  J. Jansson,et al.  von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death , 1992, British heart journal.

[28]  J. Jansson,et al.  von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. , 1991, British heart journal.

[29]  D. Tate,et al.  von Willebrand factor and occlusive arterial thrombosis. A study in normal and von Willebrand's disease pigs with diet-induced hypercholesterolemia and atherosclerosis. , 1990, Arteriosclerosis.

[30]  J M Sorace,et al.  Structure of the gene for human von Willebrand factor. , 1989, The Journal of biological chemistry.

[31]  L. Limbird.  Receptors linked to inhibition of adenylate cyclase: additional signaling mechanisms , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  D. Bellinger,et al.  Prevention of occlusive coronary artery thrombosis by a murine monoclonal antibody to porcine von Willebrand factor. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[33]  W. Marks,et al.  The effect of ABO blood group on the diagnosis of von Willebrand disease. , 1987, Blood.

[34]  N. Blin,et al.  A general method for isolation of high molecular weight DNA from eukaryotes. , 1976, Nucleic acids research.

[35]  J. Nigg,et al.  Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. , 2005, Molecular psychiatry.

[36]  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.

[37]  D. Lovinger,et al.  Alpha 2-adrenergic receptor subtypes: subtle mutation of the alpha 2A-adrenergic receptor in vivo by gene targeting strategies reveals the role of this subtype in multiple physiological settings. , 1998, Recent progress in hormone research.

[38]  U. Vischer,et al.  Epinephrine Induces von Willebrand Factor Release from Cultured Endothelial Cells: Involvement of Cyclic AMP-dependent Signalling in Exocytosis , 1997, Thrombosis and Haemostasis.

[39]  A. Schmarda,et al.  ABO glycosyltransferase genotyping by polymerase chain reaction using sequence-specific primers. , 1996, Blood.

[40]  J. Brassard,et al.  Effect of exercise, DDAVP, and epinephrine on the factor VIII:C/von Willebrand factor complex in normal dogs and von Willebrand factor deficient Doberman pinscher dogs. , 1990, Thrombosis research.