Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C‐deficient family

“…Levels of plasma VWF have been shown to be largely determined by genetic factors, with estimates of heritability in humans ranging from 25% to 32% by pedigree analysis, 7,8 to 66% to 75% in twin studies. 9,10 ABO blood group is responsible for one-third of the genetic variability in VWF plasma levels.…”

Section: Introductionmentioning

confidence: 99%

Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice

Shavit

Manichaikul

Lemmerhirt³

et al. 2009

Blood

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Type 1 von Willebrand disease (VWD) is the most common inherited human bleeding disorder. However, diagnosis is complicated by incomplete penetrance and variable expressivity, as well as wide variation in von Willebrand factor (VWF) levels among the normal population. Previous work has exploited the highly variable plasma VWF levels among inbred strains of mice to identify 2 major regulators, Mvwf1 and Mvwf2 (modifier of VWF).Mvwf1 is a glycosyltransferase and Mvwf2 is a natural variant in Vwf that alters biosynthesis. We report the identification of an additional alteration at the Vwf locus (Mvwf5), as well as 2 loci unlinked to Vwf (Mvwf6-7) using a backcross approach with the inbred mouse strains WSB/EiJ and C57BL/6J. Through positional cloning, we show that Mvwf5 is a cis-regulatory variant that alters Vwf mRNA expression. A similar mechanism could potentially explain a significant percentage of human VWD cases, especially those with no detectable mutation in the VWF coding sequence. Mvwf6 displays conservation of synteny with potential VWF modifier loci identified in human pedigrees, suggesting that its ortholog may modify VWF in human populations. Introductionvon Willebrand factor (VWF) is a central component of hemostasis, serving as the adhesive link between platelets and the injured blood vessel wall, as well as the carrier for factor VIII. Deficiencies in VWF result in von Willebrand disease (VWD), the most common inherited bleeding disorder in humans. Elevated VWF levels may also be an important risk factor for thrombosis, both through a direct role in platelet adhesion, 1 as well as indirectly by causing elevated levels of factor VIII. [2][3][4] Diagnosis of VWD is elusive in many cases because of its variable expressivity and incomplete penetrance 5 and the nonspecific nature of bleeding symptoms. 6 VWF plasma protein levels also display a broad distribution in the normal human population. Thus, it is often difficult to determine whether a person has VWD and is at risk for pathologic hemorrhage or simply has VWF levels in the low range of normal.Levels of plasma VWF have been shown to be largely determined by genetic factors, with estimates of heritability in humans ranging from 25% to 32% by pedigree analysis, 7,8 to 66% to 75% in twin studies. 9,10 ABO blood group is responsible for one-third of the genetic variability in VWF plasma levels. 11 However, the loci responsible for the remaining two-thirds of this genetic component are unknown. Recent evidence from European and Canadian cooperative studies on type 1 VWD have found that disease diagnosis does not segregate with VWF genotype in approximately 50% of families, supporting the existence of additional genetic factors. [12][13][14][15][16] Laboratory mice display wide variation in VWF levels with 65% heritability in a cross between the strains A/J and CASA/RkJ, 17 strikingly similar to the estimates for humans derived from twin studies. 9,10 This variability among inbred mouse strains has been used to identify genetic loci modifying VWF level...

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“…1 All the genes encoding hemostatic factors are potential candidates for thrombosis and studies in families and twins have demonstrated significant contributions of additive genetic factors to variance in these intermediate phenotypes. [2][3][4][5][6][7][8][9] Significant genetic correlations between hemostatic factors and thrombosis were identified in the GAIT study, indicating shared genes regulate plasma levels of hemostatic factors and susceptibility to thrombosis. 1 Although genetic factors contribute to variance in hemostatic factors, associations between common genetic variants of the genes encoding a variety of hemostatic components and CVD have generally been inconsistent.…”

mentioning

confidence: 99%

Heritability of Clot Formation, Morphology, and Lysis

Carter

Cymbalista

Spector

et al. 2007

ATVB

155

152

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Objective-The relative balance between clot formation and fibrinolysis is considered to reflect thrombotic potential following vascular injury. The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study, and (2) Key Words: heritability Ⅲ coagulation Ⅲ fibrinolysis Ⅲ metabolic syndrome Ⅲ cardiovascular disease T he development of cardiovascular disease (CVD) is associated with a major thrombotic component initiated by underlying vascular damage. In occlusive arterial disease the development of a platelet rich thrombus is supported by a fibrin mesh, with fibrin formation dependent on complex interactions between components of the coagulation cascade. A significant contribution of additive genetic factors in determining risk for thrombosis was indicated by the GAIT Study, in which genetic factors accounted for Ϸ60% of variation in risk. 1 All the genes encoding hemostatic factors are potential candidates for thrombosis and studies in families and twins have demonstrated significant contributions of additive genetic factors to variance in these intermediate phenotypes. [2][3][4][5][6][7][8][9] Significant genetic correlations between hemostatic factors and thrombosis were identified in the GAIT study, indicating shared genes regulate plasma levels of hemostatic factors and susceptibility to thrombosis. 1 Although genetic factors contribute to variance in hemostatic factors, associations between common genetic variants of the genes encoding a variety of hemostatic components and CVD have generally been inconsistent. 10 Clot formation and fibrinolysis are dynamic processes, and identification of genetic factors regulating individual hemostatic factors may be less informative in relation to cardiovascular risk than identifying genetic factors influencing more complex phenotypes reflecting fibrin structure/function. A study in twins indicated heritabilities of 0.39 and 0.46 for clot permeability and clot density, 11 suggesting that genetic factors are important determinants of these phenotypes.The limited studies which have evaluated fibrin clot structure/function in relation to CVD indicate that dense structures, with increased stiffness, decreased permeability, and decreased clot lysis are observed in subjects with CVD 12,13 and in relatives of individuals with CVD. 14 Further understanding of the genetic and environmental determinants of fibrin structure/function may help to identify novel factors which influence vascular risk, and, in the longer term, inform the development of novel therapeutics.The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study and (2) to determine the relationship between measures of clot structure/function and the metabolic syndrome as an indicator of cardiovascular risk.

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Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C‐deficient family

Cited by 71 publications

References 43 publications

Investigation of von Willebrand Factor Gene Mutations in Korean von Willebrand Disease Patients

Investigation of von Willebrand Factor Gene Mutations in Korean von Willebrand Disease Patients

Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice

Heritability of Clot Formation, Morphology, and Lysis

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