Blood Journal
Leading the way in experimental and clinical research in hematology

Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC study

  1. Marco Campos1,
  2. Ashley Buchanan2,
  3. Fuli Yu3,
  4. Maja Barbalic4,
  5. Yang Xiao5,
  6. Lloyd E. Chambless2,
  7. Kenneth K. Wu6,
  8. Aaron R. Folsom7,
  9. Eric Boerwinkle4, and
  10. Jing-fei Dong5,*
  1. 1 Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States;
  2. 2 Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States;
  3. 3 Human Genome Sequencing Center, Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX, United States;
  4. 4 Human Genetic Center, University of Texas School of Public Health, Houston, TX, United States;
  5. 5 Puget Sound Blood Center, Seattle, WA, United States;
  6. 6 National Health Research Institutes, Taipei, Taiwan;
  7. 7 Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States
  1. * Corresponding author; email: jfdong{at}


Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and -independent mechanisms. SNPs of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion and activity, but impacts of non-disease causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10,434 healthy Americans of European (EA) or African (AA) descents in the Atherosclerosis Risk in Communities study. Among covariates, age, race, diabetes and ABO contributed 2.2%, 3.5%, 4% and 10.7% to FVIII inter-subject variation, respectively. Four intronic FVIII SNPs associated with FVIII activity and eight with FVIII-VWF ratio in a gender- and race-dependent manner. The FVIII haplotypes AT and GCTTTT also associated with FVIII activity. Seven VWF SNPs were associated with FVIII activity in EA subjects, but no FVIII SNPs were associated with VWF antigen. These data demonstrate that intronic SNPs could directly or indirectly influence inter-subject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity.

  • Submitted October 3, 2011.
  • Accepted December 18, 2011.