ABO blood groups are known to influence the plasma level of von Willebrand factor (VWF), but little is known about the relationship between ABO and coagulation factor VIII (FVIII). We analyzed the influence of ABO genotypes on VWF antigen, FVIII activity, and their quantitative relationship in 11,673 participants in the Atherosclerosis Risk in Communities (ARIC) study. VWF, FVIII, and FVIII/VWF levels varied significantly among O, A (A1 and A2), B and AB subjects, and the extent of which varied between Americans of European (EA) and African (AA) descent. We validated a strong influence of ABO blood type on VWF levels (15.2%), but also detected a direct ABO influence on FVIII activity (0.6%) and FVIII/VWF ratio (3.8%) after adjustment for VWF. We determined that FVIII activity changed 0.54% for every 1% change in VWF antigen level. This VWF-FVIII relationship differed between subjects with O and B blood types in EA, AA, and in male, but not female subjects. Variations in FVIII activity were primarily detected at low VWF levels. These new quantitative influences on VWF, FVIII and the FVIII/VWF ratio help understand how ABO genotypes differentially influence VWF, FVIII and their ratio, particularly in racial and gender specific manners.
IntroductionThe von Willebrand factor (VWF) is an essential component of hemostasis at sites of vascular injury. This hemostatically active adhesion ligand also plays a critical role in thrombus formation at the site of a ruptured atherosclerotic plaque and in platelet aggregation induced by high fluid shear stress in areas of severe vascular stenosis. The former results in myocardial infarction when it occurs in coronary arteries, whereas the latter is a major cause of thromboembolism associated with ischemic stroke. 1 VWF is the largest multimeric glycoprotein in the plasma. It is exclusively synthesized in endothelial cells and megakaryocytes initially as a monomeric glycoprotein. In the endoplasmic reticulum and Golgi apparatus of these cells, the monomers form C-terminal disulfide-linked dimers. A various number of dimers subsequently form multimers through N-terminal disulfide linkages, a process assisted by the proteolytic release of a 714-amino acid propeptide. 2,3 The newly synthesized VWF multimers are either constitutively released into the circulation or stored in the Weibel-Palade bodies of endothelial cells and ␣-granules of megakaryocytes/platelets. 4,5 On stimulation, these granules secrete the stored VWF multimers that are rich in ultra-large and hemostatically hyperactive forms. 4,6 Ultra-large VWF multimers are also secreted under endothelial stress caused by inflammation but are rapidly and partially cleaved by the zinc metalloprotease AD-AMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) into smaller, variable-sized multimers. 7-9 The hemostatic activity of VWF multimers is determined not only by multimer size, 4,10 but also by the quantity of VWF antigen in the circulation. The plasma level of VWF multimers is determined by a dynamic balance between the rate of production and that of clearance. Although acquired conditions are known to affect synthesis and secretion, 11 genetic factors play a major role in regulating VWF synthesis and clearance. It has been reported that genetic factors are responsible for up to 66% of variation in plasma VWF antigen level, of which 30% is related to ABO blood type. 12,13 The human VWF gene is located on chromosome 12. 14,15 It spans approximately 180 kb of nucleotides and contains 52 exons that encode a multidomain prepolypeptide of 2791 amino acids. [14][15][16] The VWF gene is highly polymorphic. 17 Single nucleotide polymorphisms (SNPs) of the coding and promoter sequences in the VWF gene have been extensively studied and found to influence the levels of VWF in the circulation. Furthermore, as a heavily glycosylated polypeptide, 16,18 the level of circulating VWF is also affected by the structure of its carbohydrate side chains, which are associated with ABO blood group, primarily because of the presence or absence of a functional glycosyltransferase that adds either a N-acetylgalactosamine or a D-galactose to a D-galactose side chain on the H antigen. 19 This structural variation in glycosylation has been reported to directly...
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. Single nucleotide polymorphisms (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) descent in the Atherosclerosis Risk in Communities (ARIC) study. Among covariates, age, race, diabetes, and ABO contributed 2.2%, 3.5%, 4%, and 10.7% to FVIII intersubject variation, respectively. Four intronic FVIII SNPs associated with FVIII activity and 8 with FVIII-VWF ratio in a sex- 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 Ag. These data demonstrate that intronic SNPs could directly or indirectly influence intersubject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity.
The synthesis, secretion and clearance of von Willebrand factor (VWF) are regulated by genetic variations in coding and promoter regions of the VWF gene. We have previously identified 19 single nucleotide polymorphisms (SNPs), primarily in introns that are associated with VWF antigen levels in subjects of European descent. In this study, we conducted race by gender analyses to compare the association of VWF SNPs with VWF antigen among 10,434 healthy Americans of European (EA) or African (AA) descent from the Atherosclerosis Risk in Communities (ARIC) study. Among 75 SNPs analyzed, 13 and 10 SNPs were associated with VWF antigen levels in EA male and EA female subjects, respectively. However, only one SNP (RS1063857) was significantly associated with VWF antigen in AA females and none was in AA males. Haplotype analysis of the ARIC samples and studying racial diversities in the VWF gene from the 1000 genomes database suggest a greater degree of variations in the VWF gene in AA subjects as compared to EA subjects. Together, these data suggest potential race and gender divergence in regulating VWF expression by genetic variations.
4310 Background and Objectives: Von Willebrand factor (VWF) is an essential component of hemostasis. It is known that multimer size and the amount of circulating VWF impact its hemostatic function. Genetic factors play a major role in regulating VWF synthesis and clearance and are reported to contribute to 66% of the variation in plasma VWF antigen level. We have analyzed 78 SNPs distributed throughout the VWF gene and haplotypes constructed from those SNPs for an association with VWF antigen level in 7,856 subjects of European descent in the Atherosclerosis Risk in Communities cohort. Methods and Results: Blood was drawn after an 8 hour fasting period and VWF antigen level was determined by a commercial ELISA kit. All subjects underwent analysis for 78 SNPs available from Affymetrix 6.0 chip in the region encompassing the VWF gene. We used the fastPHASE 1.2 program to resolve haplotypes from the unphased SNP genotype data. Using Haploview we determined SNPs in strong linkage disequilibrium (LD), their co-segregation rates and underlying haplotypes. Linear models were used to evaluate the association of actual or log VWF antigen levels with each SNP and haplotypes derived from those SNPs. Eighteen (16 are intronic) of the 78 SNPs were found to significantly associate with levels of VWF antigen (Table 1). All are clustered in a 50 kb region of the VWF gene in spite of the fact that the 78 SNPs studied are distributed throughout the VWF gene without apparent clusters. All 78 SNPs are co-segregated in 9 LD haplotype blocks, but a majority of positive SNPs (88.9%) are located in Block 5 and 6, which significantly correlate with VWF antigen level. The O blood type contributes to ∼ 15% of variation in VWF antigen levels. The association for SNPs and Haplotypes grows stronger after ABO effects are removed. Among non-genomic factors, age and BMI are the most significant factors and contribute to 4.8% and 1.4% of variation in VWF antigen level. Conclusions: We have found a strongly positive association between VWF level and SNPs and haplotypes from a strikingly concentrated region of the VWF gene. This region encodes the D2, D' and D3 domains of VWF, including the propeptide and multimerization and Factor VIII binding sites. The physiological significance of these clustered SNPs on VWF synthesis or clearance remains to be further investigated. Our data suggest that this region plays an important role in regulating VWF antigen level and support the idea that combinations of SNPs in LD can provide additive affects. Disclosures: No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.