Genome-wide linkage analysis of von Willebrand factor plasma levels: results from the GAIT project

 

 Buy Article Permissions and Reprints

Summary

High plasma levels of von Willebrand factor (vWF) have been associated with the risk of thromboembolic disease. As a complex trait, this phenotype must be influenced by genetic and environmental factors. Among the genetic factors, only the ABO gene located on chromosome 9q34 has been clearly linked to the plasma levels of vWF. This locus explains about 30-40% of the genetic variability. Therefore, the source of the majority of the genetic component remains to be identified.

To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in vWF levels in 21 Spanish families as part of the GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project.

The results showed that the strongest linkage signal (LOD = 3.46, p = 0.00003) for vWF was found on chromosome 9q34 at the DNA marker D9S290, where the ABO gene is located. Additional suggestive linkage signals were found on chromosomes 2q23.2 (LOD = 1.65, p = 0.003) and 1p36.13 (LOD = 1.32, p = 0.007). After refining the linkage analysis, conditional to the ABO genotype, three additional loci on chromosomes 5, 6 and 22 showed LOD scores higher than 1, suggesting the presence of other genes linked to vWF levels. Curiously, no linkage signals were detected in other chromosome regions previously associated with vWF levels (like the structural VWF gene on 12p13.2 or Lewis blood group gene on 19q13). These results indicate that these loci are not important genetic determinants of the normal variation of vWF levels.

Our results indicate that the ABO locus is the major genetic determinant of the plasma levels of the vWF in Spanish population. It is possible that there are other potential regions on chromosomes 1, 2, 5, 6 and 22 that influence this thrombosis risk factor. However, the structural vWF gene itself has a very low influence (if any) on the plasma levels of vWF.

• References

• 1 Sadler JE, Mannucci PM, Berntorp E, Bochkov N, Boulyjenkov V, Ginsburg D, Meyer D, Peake I, Rodeghiero F, Srivastava A. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160-74.
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 Ginsburg D, Handin RL, Bonthron DT, Don-lon TA, Bruns GAP, Latt SA, Orkin SH. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228: 1401-6.
  CrossrefPubMedGoogle Scholar
• 3 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
  CrossrefPubMedGoogle Scholar
• 4 O’Donell J, Tuddenham EGD, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-8.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: the atherosclerosis risk in communities (ARIC) study. Circulation 1997; 96: 1102-8.
  CrossrefPubMedGoogle Scholar
• 6 Souto JC, Almasy L, Borrell M, Blanco-Vaca F, Mateo J, Soria JM, Coll I, Felices R, Stone W, Fontcuberta J, Blangero J. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT Study. Am J Hum Genet 2000; 67: 1452-9.
  CrossrefPubMedGoogle Scholar
• 7 Levy G, Ginsburg D. Getting at the variable expressivity of von Willebrand disease. Thromb Haemost 2001; 86: 144-8.
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Souto JC, Almasy L, Borrell M, Garí M, Martínez E, Mateo J, Stone WH, Blangero J, Fontcuberta J. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546-51.
  CrossrefPubMedGoogle Scholar
• 9 O’Donnell J, Laffan MA. The relationship between ABO histo-blood group, factor VIII and von Willebrand factor. Transfus Med 2001; 11: 343-51.
  CrossrefPubMedGoogle Scholar
• 10 O’Donnell J, Boulton FE, Manning RA, Laffan MA. Amount of H antigen expressed on circulating von Willebrand factor is modified by ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels. Arterioscler Thromb Vasc Biol 2002; 22: 335-41.
  CrossrefPubMedGoogle Scholar
• 11 Souto JC, Almasy L, Muñiz-Diaz E, Soria JM, Borrell M, Bayén L, Mateo J, Madoz P, Stone W, Blangero J, Fontcuberta J. Functional effects of the ABO locus polymorphism on plasma levels of von Willebrand factor, factor VIII, and activated partial thromboplastin time. Arterioscler Thromb Vasc Biol 2000; 20: 2024-8.
  CrossrefPubMedGoogle Scholar
• 12 Orstavik KH, Magnus P, Reisner H, Berg K, Graham JB, Nance W. Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985; 37: 89-101.
  PubMedGoogle Scholar
• 13 Mohlke KL, Purkayastha AA, Westrick RJ, Smith PL, Petryniak B, Lowe JB, Ginsburg D. Mvwf a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase. Cell 1999; 96: 111-20.
  CrossrefPubMedGoogle Scholar
• 14 Sodetz JM, Paulson JC, McKee PA. Carbohydrate composition and identification of blood group A, B and H oligossacharide structures on human factor VIII/von Willebrand factor. J Biol Chem 1979; 254: 10754-60.
  PubMedGoogle Scholar
• 15 Keightley AM, Lam YM, Brady JN, Cameron C, Lillicrap D. 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 1999; 93: 4277-83.
  PubMedGoogle Scholar
• 16 Harvey PJ, Keightley AM, Lam YM, Cameron C, Lillicrap D. A single nucleotide polymorphism at nucleotide-1793 in the von Wille-brand factor (VWF) regulatory region is associated with plasma VWF:Ag levels. Br J Haematol 2000; 109: 349-3.
  CrossrefPubMedGoogle Scholar
• 17 Boerwinkle E, Chakraborty R, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man, I: models and analytical methods. Ann Hum Genet 1986; 50: 81-94.
  PubMedGoogle Scholar
• 18 Almasy L, Hixson JE, Rainwater DL, Cole S, Williams JT, Mahaney MC, Vanderberg JL, Stern MP, MacCluer JW, Blangero J. Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism. Am J Hum Genet 1999; 64: 1686-93.
  CrossrefPubMedGoogle Scholar
• 19 Erketin-Taner N, Graff-Radford N, Younkin LH, Eckman Ch, Baker M, Adamson J, Ronald J, Blangero J, Hutton M, Younkin SG. Linkage of plasma A 42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 2000; 290: 2303-4.
  CrossrefPubMedGoogle Scholar
• 20 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988; 16: 1215
  CrossrefPubMedGoogle Scholar
• 21 Dyke B. PEDSYS: a pedigree data management system. User’s manual. PGL Tech rep 2. Population Laboratory, Department of Genetics, Southwest Foundation for Biomedical Research: San Antonio; 1995
  Google Scholar
• 22 Allison DB, Neale MC, Zannolli R, Schork NJ, Amos CI, Blangero J. Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure. Am J Hum Genet 1999; 65: 531-44.
  CrossrefPubMedGoogle Scholar
• 23 Blangero J, Williams JT, Almasy L. Robust LOD scores for variance component-based linkage analysis. Genet Epidemiol 2000; 19: S8-S14.
  CrossrefPubMedGoogle Scholar
• 24 Almasy L, Blangero JC. Multipoint quantitative trait linkage analysis in general pedigrees. Am J Hum Genet 1998; 62: 1198-211.
  CrossrefPubMedGoogle Scholar
• 25 Self SG, Liang K-Y. Asymptotic properties of maximum likelihood estimators and likelihood ratio tests under non-standard conditions. J Am Stat Assoc 1987; 82: 605-10.
  CrossrefPubMedGoogle Scholar
• 26 Boehnke M, Lange K. Ascertainment and goodness of fit of variance component models for pedigree data. Prog Clin Biol Res 1984; 147: 173-92.
  PubMedGoogle Scholar
• 27 Gambaro G, Anglani F, D’Angelo A. Association studies of genetic polymorphisms and complex disease. Lancet 2000; 355: 308-11.
  CrossrefPubMedGoogle Scholar
• 28 Almasy L, MacCluer JW. Association studies of vascular phenotypes. How and why?. Arterioscler Thromb Vasc Biol 2002; 22: 1055-7.
  CrossrefPubMedGoogle Scholar
• 29 O’Donnell JS, Boulton FE, Manning RA, Laffan MA. Concordant FVIII:VWF ratio across ABO blood group genotypes suggests the effect of the ABO locus on plasma FVIII/VWF levels is mediated by rate of clearance. Thromb Haemost 2001; (Suppl) abstract P223.
  PubMedGoogle Scholar
• 30 Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Le Beau MM, Sorace JM, Sadler JE. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30: 253-69.
  CrossrefPubMedGoogle Scholar
• 31 Orstavik KH, Kornstad L, Reisner H, Berg K. Possible effect of secretor locus on plasma concentration of factor VIII and von Wille-brand factor. Blood 1989; 73: 990-3.
  PubMedGoogle Scholar
• 32 O’Donnell JS, Boulton FE, Manning RA, Laffan MA. Secretor blood group genotype does not influence plasma concentration of factor VIII or von Willebrand factor. Thromb Haemost 2001; (Suppl); abstract P229.
  PubMedGoogle Scholar
• 33 Blangero B, Williams JT, Almasy L. Quantitative trait locus mapping using human pedigrees. Hum Biol 2000; 72: 35-62.
  PubMedGoogle Scholar
• 34 Sham PC, Cherny SS, Purcell S, Hewitt JK. Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data. Am J Hum Genet 2000; 66: 1616-30.
  CrossrefPubMedGoogle Scholar