Microsatellite (GT)_n repeats and SNPs in the von Willebrand factor gene promoter do not influence circulating von Willebrand factor levels under normal conditions

Summary

Von Willebrand factor (VWF) levels vary considerably in normal individuals, influenced by inherited and acquired modulators. ABO blood group is the major inherited determinant of VWF levels, but a role has also been attributed to the VWF gene promoter, haplotype 1 (-3268G/-2709C/-2661A/-2527G) being associated with higher VWF levels than haplotype 2 (-3268C/-2709T/-2661G/-2527A), and the polymorphic locus (GT)_n modulating the shear stress-induced activation of the VWF promoter. We characterized the (GT)_n of the VWF promoter in 394 healthy individuals and assessed whether its variable length influenced VWF levels in normal conditions. (GT)_n proved highly polymorphic, with alleles from 15 to 24 repeats long. (GT)₂₁ and (GT)₁₉ were the most common variants (37.4% and 34.4%, respectively). Short GT repeats (15–19) segregated mainly with haplotype 1, long GT repeats (20–24) with haplotype 2 (p<0.0001). The number of GT repeats did not correlate with VWF levels, nor did such levels correlate with haplotypes 1 and 2, considered alone or in association with the (GT)_n locus. We conclude that (GT)_n and -3268/-2709/-2661/-2527 loci are in strong linkage disequilibrium. This polymorphic region of the VWF promoter does not affect VWF levels under normal conditions, though it might represent an environmentally activable VWF regulation site.

Keywords

von Willebrand factor - (GT)_n locus - VWF promoter SNPs - linkage disequilibrium - VWF level variability

• References

• 1 Ruggeri ZM. Von Willebrand factor. Curr Opin Hematol 2003; 10: 142-149.
• 2 Sadler JE. Biochemistry and genetics of von Wille-brand factor. Ann Rev Biochem 1998; 67: 395-424.
• 3 Foster PA, Fulcher CA, Marti T. et al. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem 1987; 262: 8443-8446.
• 4 De Lange M, Snieder H, Ariens R. et al. The genetics of haemostasis. Lancet 2001; 357: 101-105.
• 5 Gill JC, Endres-Brooks J, Bauer PJ. The effect of ABO blood group in the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695.
• 6 Aillaud MF, Pignol F, Alessi MC. et al. Increase in plasma concentration of plasminogen activator inhibitor, fibrinogen, von Willebrand factor, factor VIII:C and in erythrocyte sedimentation rate with age. Thromb Haemost 1986; 55: 330-332.
• 7 Miller CH, Haff E, Platt SJ, Rawlins P, Drews CD, Dilley AB, Evatt B. Measurement of von Willebrand factor activity: relative effects of ABO blood type and race. J Thromb Haemost. 2003; 1: 2191-21977.
• 8 Stirling Y, Woolf L, North WR. et al. Hemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176-182.
• 9 Pottinger BE, Read RC, Paleolog EM. et al. Von Willebrand factor is an acute phase reactant in man. Thromb Res 1989; 53: 387-394.
• 10 Sadler JE. New concepts in von Willebrand disease. Ann Rev Med 2005; 56: 173-191.
• 11 Lip GY, Blann AD. (1995) Von Willebrand factor and its relevance to cardiovascular disorders. Brit Heart J 1995; 74: 580-583.
• 12 Jager A, van Hinsbergh VW, Kostense PJ. et al. Von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscler Thromb Vasc Biol 1999; 109: 1343-1348.
• 13 Martinelli I. Von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis. Semin Hematol 2005; 42: 49-55.
• 14 Keightley AM, Lam YM, Brady JN. et al. Variation at the von Willebrand factor (VWF) gene locus is associated with plasma VWF levels: identification of three novel single nucleotide polymorphisms in the VWF gene promoter. Blood 1999; 93: 4277-4283.
• 15 Harvey PJ, Keightley AM, Lam YM. et al. A single nucleotide polymorphism at nucleotide –1793 in the von Willebrand factor (VWF) regulatory region is associated with plasma VWF:Ag levels. Brit J Haematol 2000; 109: 349-353.
• 16 Casonato A, Daidone V, Sartorello F. et al. Polymorphisms in von Willebrand factor gene promoter influence the glucocorticoid-induced increase in von Willebrand factor: the lesson learned from Cushing syndrome. Brit J Haematol 2008; 140: 230-235.
• 17 Hough C, Cameron CL, Notley CR. et al. Influence of a GT repeat element on shear stress responsiveness of the VWF gene promoter. J Thromb Haemost 2008; 6: 1183-1190.
• 18 Casonato A, Sartorello F, Pontara E. et al. A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: an elusive phenotype and a difficult diagnosis. Thromb Haemost 2007; 98: 1182-1187.
• 19 Mancuso DJ, Tuley EA, Westfield LA. et al. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-19527.
• 20 Goodeve AC, Eikenboom JC, Ginsburg D. et al ISTH SSC Subcommittee on von Willebrand factor.. A standard nomenclature for von Willebrand factor gene mutations and polymorphisms. On behalf of the ISTH SSC Subcommittee on von Willebrand factor. Thromb Haemost 2001; 85: 929-931.
• 21 Gallinaro L, Cattini MG, Sztukowska M, Padrini R, Sartorello F, Pontara E, Bertomoro A, Daidone V, Pagnan A, Casonato A. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111: 3540-3545.
• 22 Bennett P. Demystified ... microsatellites. Mol Path 2000; 53: 177-183.
• 23 Rich A, Zhang S. Timeline: Z-DNA: the long road to biological function. Nat Rev Genet 2003; 4: 566-572.
• 24 Eikenboom JC, Castaman G, Vos HL. et al. Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb Haemost 1998; 79: 709-717.
• 25 Casana P, Martínez F, Haya S, Espinós C, Aznar JA. Significant linkage and non-linkage of type 1 von Willebrand disease to the von Willebrand factor gene. Br J Haematol 2001; 115: 692-700.
• 26 Zhang ZP, Deng LP, Blombäck M. et al. Dinucleo-tide repeat polymorphism in the promoter region of the human von Willebrand factor gene (vWF gene). Hum Mol Genet 1992; 1: 780.
• 27 Venables WN, Ripley BD. Modern Applied Statistics with S. Fourth edition. Springer; 2002