Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

Abstract

The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the "missing heritability" for other complex genetic traits.genome-wide association study | linkage study | venous thromboembolic disease | von Willebrand disease | quantitative trait loci V on Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a central role in hemostasis by acting as a molecular bridge tethering platelets to injured endothelium and as a carrier molecule for coagulation factor VIII (1). Quantitative or qualitative deficiencies in VWF lead to von Willebrand Disease (VWD), the most common inherited bleeding disorder, with an estimated prevalence of 0.002-0.01% worldwide (1, 2). Type I VWD is characterized by mild to moderate bleeding and low circulating VWF levels. This form of VWD is generally associated with haploinsufficiency for VWF and is characterized by incomplete penetrance. In contrast, elevated levels of plasma VWF are an independent risk factor for venous thromboembolic disease (3), myocardial infarction (4), stroke (5, 6), and also complicate anticoagulant management (7).Plasma VWF levels vary by approximately fivefold in healthy populations and are influenced by both environmental and inherited factors. Increased levels of VWF occur with advancing age (8), may rise acutely because of inflammation or infection, and may serve as a surrogate marker for endothelial dysfunction and atherosclerosis (9-11). Estimates for the heritability of plasma VWF levels in the general population from previous family-based studies range from 32-75%. A 1985 study in Norwegian twins reported the heritability of VWF at 66%, with 30% of this effect attributable to ABO blood type (12). More recent studies estimated the heritabil...

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

“…Indeed, carriers of the B antigen have higher VWF levels compared with carriers of the A antigen and carriers of both antigens have the highest VWF levels. 33, 34 The second locus is within the VWF gene. It has been well established that common genetic polymorphisms in the VWF gene contribute to the variability in VWF:Ag levels.…”

A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

“…1 The VWF level we observed in C57BL/ 6J mice (3.4 mg/mL, Figure 2A) is ;1/3 of the average VWF level in healthy humans, consistent with a previous report. 40 Whereas VWF levels in healthy humans range ;3-fold (from ;5 to ;15 mg/mL), 41 VWF levels among inbred mouse strains vary even more widely (.10-fold). 30 This latter variation is due to differences in VWF synthesis/secretion and clearance among mouse strains.…”

Köpeklerde von Willebrand Faktör Antijen Seviyesi ve von Willebrand Faktör Geni Arasındaki İlişkinin Belirlenmesi

“…The encode of VWF is located on short arm of chromosome 12 and the 52 exons of the gene in humans [9,26] . The single-gene associations between plasma vWF: Ag concentrations and variants at the angiotensin-coverting enzyme, the FUR2 locus, lipoproteinreceptor-related protein, and arginine vasopressin 2 receptor have been reported in previous studies in humans [16] . Kramer et al [3] investigated German Shorthaired Pointers having type II vWD and they found statistical importance between vWF variant nucleotide in exon 28 and vWF multimer deficiencies.…”

“…Von Willebrand's disease is an acquired or inherited bleeding disorder common in humans and dogs [3] . In human beings estimated prevalence of vWD has been reported between 0.01-0.02% [9,16] . Castaman et al [17] point out that with a prevalence of 1% in general population; the ratio of visible clinical symptoms is only 0.01%.…”

“…However, Slappendel et al [22] speculated that plasma vWF: Ag levels ranged between 30 to 89% in 39 Dutch kookier dogs are obligate carriers of Type III vWD. In addition, in people for the estimates of the heritability is used as plasma vWF: Ag levels in between 35-75% [16] . Because of the uncertainty in defining carrier status by ELISA method measuring vWF: Ag concentration in plasma, the location and character of the mutation causing vWD should be determined [3] .…”