Abstract
von Willebrand factor (VWF) is a complex multimeric plasma glycoprotein encoded by an approximately 178-kb large VWF gene located on the short arm of chromosome 12 (12p13.2). VWF plays an important role in hemostasis through binding with platelet GpIbα receptors. We made an attempt to correlate the 789Ala/Ala genotype of the VWF with VWF:Ag level in different types of unrelated von Willebrand disease (VWD) patients and healthy controls. VWF assays and other coagulation screening tests have been done for all 103 (50 male, 53 female) different types of index VWD patients including 19 type 1, 55 type 2, and 29 type 3 VWD patients. Genotypes were detected by polymerase chain reactions followed by restriction fragment length polymorphism. The genotype 789Ala/Ala was found in 26.3% type 1 and in 31.0% type 3 patients. This genotype was not found in any of type 2 patient or healthy controls. Overall, 789Ala/Ala genotype was found significantly higher (P < 0.001) in quantitative type (type 1 and type 3) VWD that is occurred due to low VWF:Ag level. These results demonstrate that mutant homozygous 789Ala/Ala genotype of this polymorphism probably have their functional implications for low plasma VWF:Ag level in quantitative type of VWD.
Similar content being viewed by others
References
Sadler JE, Mannucci PM, Berntorp E et al (2000) Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 84:160–174
Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC (1993) Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 123:893–898 doi:10.1016/S0022-3476(05)80384-1
Ruggeri ZM (2003) Von Willebrand factor. Curr Opin Hematol 10:142–149 doi:10.1097/00062752-200303000-00008
Sadler JE (1998) Biochemistry and genetics of von Willebrand factors. Annu Rev Biochem 67:395–424 doi:10.1146/annurev.biochem.67.1.395
Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L et al (2006) Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 4:2103–2114 doi:10.1111/j.1538-7836.2006.02146.x
Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Le Beau MM, Sorace JM et al (1991) Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 30:253–269 doi:10.1021/bi00215a036
Kunkel GR, Graham JB, Fowlkes DM, Lord ST (1990) RsaI polymorphism in von Willebrand factor (VWF) at codon 789. Nucleic Acids Res 18:4961 doi:10.1093/nar/18.16.4961-a
Bowen DJ, Collins PW (2003) An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Blood 103:941–947 doi:10.1182/blood-2003-05-1505
Davies JA, Bowen DJ (2007) The association between the L1565 genotype of von Willebrand factor and susceptibility to proteolysis by ADAMTS13. Haematologica 92:240–243 doi:10.3324/haematol.10633
Hassenpflug WA, Budde U, Obser T, Angerhaus D, Drewke E, Schneppenheim S et al (2006) Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13 dependent proteolysis. Blood 107:2339–2345 doi:10.1182/blood-2005-04-1758
Lacquemant C, Gaucher C, Delorme C et al (2000) Association between high von Willebrand factor levels and the Thr789Ala VWF gene polymorphism but not with nephropathy in type I diabetes. The GENEDIAB Study Group and the DESIR Study Group. Kidney Int 57:1437–1443 doi:10.1046/j.1523-1755.2000.00988.x
Simon D, Bandinelli E, Roisenberg I (2003) Polymorphism in the promoter region of von Willebrand factor gene and von Willebrand disease type-1. Genet Mol Biol 26:397–401 doi:10.1590/S1415-47572003000400001
Keightley AM, Lam YM, Brady JN, Cameron CL, Lillicrap D (1999) 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. Blood 93:4277–4283
Moore RE, Seidman DD, Smith JC, Struhl K (1992) Current protocols in molecular biology. Greene Publishing Associates and Wiley Interscience, New York, pp 2.1.1–2.1.7
Ivy AC, Nelson D, Buchet G (1941) The standardization of certain factors in the cutaneous ‘venostasis’ bleeding time technique. J Lab Clin Med 26:1812–1822
Macfarlane DE, Stibbe J, Kirby EP, Zucker MB, Grant RA, Mc Pherson JA (1975) A method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh 34:306–308
Graham JB, Kunkel GR, Tennyson GS, Lord ST, Fowlkes DM (1989) The Malmo polymorphism of factor IX: Establishing the genotypes by rapid analysis of DNA. Blood 73:2104–2107
Kogan SC, Doherty M, Gitschier J (1987) An improved method for prenatal diagnosis of genetic disease by analysis of amplified DNA sequence: application to hemophilia A. N Engl J Med 317:985–990
Gupta PK, Ahmad RPH, Sazawal S, Choudhry VP, Saxena R (2005) Relatively high frequency of VWD type 3 and 2 in cohort of Indian patient: the role of multimeric analysis. J Thromb Haemost 3:1321–1322 doi:10.1111/j.1538-7836.2005.01336.x
Klemm T, Mehnert AK, Siegemund A, Wiesner TD, Gelbrich G, Bluher M et al (2005) Impact of the Thr789Ala genotype 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. Exp Clin Endocrinol Diabetes 113:568–572 doi:10.1055/s-2005-872896
Harvey PJ, Keightley AM, Lam YM, Cameron C, Lillicrap D (2000) A single nucleotide polymorphism at nucleotide −1793 in the von Willebrand factor (VWF) regulatory region is associated with plasma VWF:Ag levels. Br J Haematol 109:349–353 doi:10.1046/j.1365-2141.2000.02000.x
Beranek M, Kankova K, Kolar P, Znojil V (2002) Polymorphisms in the von Willebrand factor gene are not associated with proliferative retinopathy in non-insulin-dependent diabetes mellitus. Ophthalmic Res 34:327–330 doi:10.1159/000065604
Vischer UM (2006) von Willebrand factor, endothelial dysfunction and cardiovascular disease. J Thromb Haemost 4:1186–1193 doi:10.1111/j.1538-7836.2006.01949.x
Acknowledgements
We would like to pay special thanks to Mr. Alok Divedi, Department of Biostatistics, AIIMS, New Delhi for his kind support in data analysis. We are also thankful to the Department of Science and Technology (DST) New Delhi, India for financial support provided for this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ahmad, F., Kannan, M., Biswas, A. et al. Impact of 789Ala/Ala genotype on quantitative type of von Willebrand disease. Ann Hematol 88, 479–483 (2009). https://doi.org/10.1007/s00277-008-0623-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-008-0623-4