Functional Effects of the ABO Locus Polymorphism on Plasma Levels of von Willebrand Factor, Factor VIII, and Activated Partial Thromboplastin Time

Souto, Juan Carlos; Almasy, Laura; Muñiz‐Díaz, Eduardo; Soria, José Manuel Nieto; Borrell, Montserrat; Bayén, Laia; Mateo, José; Madoz, P; Stone, W. H.; Blangero, John; Fontcuberta, Jordi

doi:10.1161/01.atv.20.8.2024

Cited by 178 publications

(146 citation statements)

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“…The main genetic variable known to be involved in vWF levels is the ABO blood system, that accounts for 30% of the genetic variance (24). Individuals of the O blood group have, on average, lower vWF levels than individuals of the non-O blood group (25)(26)(27)(28). Our results agree with the well-documented relationship between the ABO blood system and vWF levels.…”

Section: Discussionsupporting

confidence: 89%

Association studies between -1185A/G von Willebrand factor gene polymorphism and coronary artery disease

Simon

Paludo

Ghisleni

et al. 2003

Braz J Med Biol Res

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High levels of von Willebrand factor (vWF) have been associated with cardiovascular disease. The A allele of the -1185A/G polymorphism in the 5'-regulatory region of the vWF gene was associated with the highest plasma vWF levels in a normal population. To examine the association between -1185A/G polymorphism and coronary artery disease (CAD), 173 Brazilian Caucasian subjects submitted to coronary angiography were studied. Of these, 57 (33%) had normal coronary arteries (control group) and 116 (67%) had CAD (patient group). Plasma vWF levels were higher in patients (145 U/dl) than in controls (130 U/dl), but the differences were significant only for O blood group subjects. Polymerase chain reaction amplification of the 864-bp vWF promoter region followed by AccII restriction digestion was used to identify the -1185A/G genotypes. The -1185A allele frequency was 43.1% in patients and 44.7% in controls. Allele and genotype frequencies were not significantly different between patients and controls. No association was observed between the -1185A/G genotypes and plasma vWF levels in patients or controls. These results suggest that -1185A/G polymorphism is not an independent risk factor for CAD.

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Section: Discussionsupporting

confidence: 89%

Association studies between -1185A/G von Willebrand factor gene polymorphism and coronary artery disease

Simon

Paludo

Ghisleni

et al. 2003

Braz J Med Biol Res

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“…39 It has been previously shown that patients with blood type O have lower levels of measured von Willebrand factor and factor VIII; however, in our study the presence of blood type O was not associated with an increased risk of bleeding. 40 Although not significant after multivariable adjustment, the following additional clinical characteristics showed strong association with bleeding complications after LVAD implantation: age, renal dysfunction, and severe RV failure (Table 4). Patient age and history of chronic kidney disease have been previously linked with an increased bleeding risk in different clinical settings.…”

Section: Discussionmentioning

confidence: 96%

Pulsatility and the Risk of Nonsurgical Bleeding in Patients Supported With the Continuous-Flow Left Ventricular Assist Device HeartMate II

Wever-Pinzon

Selzman

Drakos

et al. 2013

Circ: Heart Failure

208

111

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Background— Bleeding is an important cause of morbidity and mortality in patients with continuous-flow left ventricular assist devices (LVADs). Reduced pulsatility has been implicated as a contributing cause. The aim of this study was to assess the effects of different degrees of pulsatility on the incidence of nonsurgical bleeding. Methods and Results— The Utah Transplantation Affiliated Hospitals (U.T.A.H.) heart failure and transplant program databases were queried for patients with end-stage heart failure who required support with the continuous-flow LVAD HeartMate II (Thoratec Corp, Pleasanton, CA) between 2004 and 2012. Pulsatility was evaluated by means of the LVAD parameter pulsatility index (PI) and by the echocardiographic assessment of aortic valve opening during the first 3 months of LVAD support. PI was analyzed as a continuous variable and also stratified according to tertiles of all the PI measurements during the study period (low PI: <4.6, intermediate PI: 4.6–5.2, and high PI: >5.2). Major nonsurgical bleeding associated with a decrease in hemoglobin ≥2 g/dL (in the absence of hemolysis) was the primary end point. A total of 134 patients (median age of 60 [interquartile range: 49–68] years, 78% men) were included. Major bleeding occurred in 33 (25%) patients (70% gastrointestinal, 21% epistaxis, 3% genitourinary, and 6% intracranial). In multivariable analysis, PI examined either as a categorical variable, low versus high PI (hazard ratio, 4.06; 95% confidence interval, 1.35–12.21; P =0.04), or as a continuous variable (hazard ratio, 0.60; 95% confidence interval, 0.40–0.92; P =0.02) was associated with an increased risk of bleeding. Conclusions— Reduced pulsatility in patients supported with the continuous-flow LVAD HeartMate II is associated with an increased risk of nonsurgical bleeding, as evaluated by PI.

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“…The complexity of FVIII levels is exemplified by its association with von Willebrand factor (VWF), 41 whose levels are determined mainly by the ABO blood group. 42 We have reported previously that genetic factors appear to be the most important determinants of quantitative variation in FVIII levels, with an additive genetic heritability of 0.4 Ϯ 0.088. 3 However, ABO blood group accounts for only a small portion of the total variation in FVIII, 42 demonstrating that other genetic factor might be involved in the quantitative variation of this important phenotype.…”

Section: Discussionmentioning

confidence: 95%

A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility

Soria

Almasy

Souto

et al. 2003

Blood

Self Cite

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Activated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia. A mutation in the F5 gene, factor V Leiden (FVL), is a major determinant of pathological APCR in some populations. However, APCR predicts risk for thrombosis independently of FVL. This suggests that other genetic factors may influence risk of thrombosis through quantitative variation in APCR. To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in APCR in the 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Conditional on FVL, the strongest linkage signal for APCR was found on chromosome 18 near D18S53. Bivariate linkage analyses with a genetically correlated trait, levels of clotting factor VIII, strengthened evidence for the chromosome 18 quantitative trait locus (QTL; logarithm of the odds [LOD], 4.5; P ‫؍‬ 3.08 ؋ 10 ؊5 ). However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1). This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 IntroductionVenous and arterial thrombosis may be life-threatening events and are of great importance in public health. Very little is known about the relative importance of genetic factors in thrombosis risk in the general population. 1 Recently, as part of the GAIT (Genetic Analysis of Idiopathic Thrombophila) project, we have quantified the genetic contribution to susceptibility to thrombosis and related phenotypes in the Spanish population. 2,3 Of the quantitative risk factors studied, activated protein C resistance (APCR) had the highest heritability (0.71), and it was genetically correlated with thrombosis ( g ϭ Ϫ 0.65; P ϭ 1 ϫ 10 Ϫ6 ), 2,3 indicating that some of the genes that influence quantitative variation in this phenotype also influence susceptibility to thrombosis.APCR is the most prevalent risk factor for thrombosis, 4 accounting for 20% to 60% of familial thrombophilia. 5 A mutation in the F5 gene (factor V Leiden [FVL]) produces a coding change from Arg506 to Gln at the first cleavage site, where APC acts to inactivate FV. As a consequence, this mutation produces a protein that is intrinsically resistant to APC, causing the APCR pathological phenotype. 6 Prevalence of FVL in different European countries ranges between 2% and 6%. 7 Moreover, APCR is a genetic risk factor for thrombosis independent of FVL. 8,9 Therefore, because of its implication in thrombotic disease, there has been a growing interest in studying other genetic factors that are likely to affect thrombosis risk through quantitative variation in this important intermediate phenotype. The APCR phenotype could theoretically result from a variety of other mutations of critical sites in the F5 or F8 genes. However, no mutations of F8 have yet been identified in patients with the APCR phenotype, 10,11 whereas 2 point ...

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Functional Effects of the ABO Locus Polymorphism on Plasma Levels of von Willebrand Factor, Factor VIII, and Activated Partial Thromboplastin Time

Cited by 178 publications

References 33 publications

Association studies between -1185A/G von Willebrand factor gene polymorphism and coronary artery disease

Association studies between -1185A/G von Willebrand factor gene polymorphism and coronary artery disease

Pulsatility and the Risk of Nonsurgical Bleeding in Patients Supported With the Continuous-Flow Left Ventricular Assist Device HeartMate II

A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility

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