Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011931
Author(s):  
Yanjun Guo ◽  
Pamela M. Rist ◽  
Maria Sabater Lleal ◽  
Paul de Vries ◽  
Nicholas Smith ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Coagulation Factor ◽  
Fibrinopeptide A ◽  
Genome Wide ◽  
Hemostatic Factors ◽  
Independent Effects ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Randomization Analysis

Objective:To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.Methods:Two-sample Mendelian randomization (MR) instrumental leveraging available genome-wide association study (GWAS) summary statistics was applied to hemostatic measures as potential causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO). Twelve blood-based measures of hemostasis were examined, including plasma level or activity of eight hemostatic factors and two fibrinopeptides together with two hemostasis clinical tests.Results:There were significant instrumental effects between increased coagulation factor VIII activity (FVIII, OR [95% CI]=1.05[1.03, 1.08]/SD, P=6.08×10-05), von Willebrand factor level (VWF, 1.05[1.03, 1.08]/SD, P=2.25×10-06), and phosphorylated fibrinopeptide A level (1.13[1.07, 1.19]/SD, P=5.44×10-06) with migraine susceptibility. When extended to migraine subtypes, FVIII, VWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76[0.64, 0.91]/SD, P=2.32×10-03) but not overall migraine. None of the hemostatic factors was linked with MO. In sensitivity analysis, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, while independent effects of FVIII and VWF could not be distinguished, and FVIIII associations were potentially affected by pleiotropy at the ABO locus. Causal effects from migraine to the hemostatic measures were not supported in reverse MR. However, MA was not included due to lack of instruments.Conclusions:The findings support potential causality of increased FVIII, VWF, and phosphorylated fibrinopeptide A, and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.

scholarly journals Influence of ABO Locus on PFA-100 Collagen-ADP Closure Time Is Not Totally Dependent on the Von Willebrand Factor. Results of a GWAS on GAIT-2 Project Phenotypes

2019 ◽  
Vol 20 (13) ◽  
pp. 3221 ◽  
Author(s):  
Núria Pujol-Moix ◽  
Angel Martinez-Perez ◽  
Maria Sabater-Lleal ◽  
Dolors Llobet ◽  
Noèlia Vilalta ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Genome Wide Association Study ◽  
Platelet Reactivity ◽  
Coagulation Factor ◽  
Nucleotide Polymorphisms ◽  
Closure Time ◽  
A Genome ◽  
Abo Genotype ◽  
Von Willebrand ◽  
Willebrand Factor

(1) Background: In a previous study, we found that two phenotypes related to platelet reactivity, measured with the PFA-100 system, were highly heritable. The aim of the present study was to identify genetic determinants that influence the variability of these phenotypes: closure time of collagen-ADP (Col-ADP) and of collagen-epinephrine (Col-Epi). (2) Methods: As part of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia (2) Project, 935 individuals from 35 large Spanish families were studied. A genome-wide association study (GWAS) with ≈ 10 M single nucleotide polymorphisms (SNPs) was carried out with Col-ADP and Col-Epi phenotypes. (3) Results: The study yielded significant genetic signals that mapped to the ABO locus. After adjusting both phenotypes for the ABO genotype, these signals disappeared. After adjusting for von Willebrand factor (VWF) or for coagulation factor VIII (FVIII), the significant signals disappeared totally for Col-Epi phenotype but only partially for Col-ADP phenotype. (4) Conclusion: Our results suggest that the ABO locus exerts the main genetic influence on PFA-100 phenotypes. However, while the effect of the ABO locus on Col-Epi phenotype is mediated through VWF and/or FVIII, the effect of the ABO locus on Col-ADP phenotype is partly produced through VWF and/or FVIII, and partly through other mechanisms.

scholarly journals Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Circulation ◽  
2019 ◽  
Vol 139 (5) ◽  
pp. 620-635 ◽  
Author(s):  
Maria Sabater-Lleal ◽  
Jennifer E. Huffman ◽  
Paul S. de Vries ◽  
Jonathan Marten ◽  
Michael A. Mastrangelo ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Plasma Levels ◽  
Coagulation Factor ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Meta Analyses ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Novel Associations

scholarly journals Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Diabetes Care ◽  
2020 ◽  
Vol 44 (1) ◽  
pp. 98-106
Author(s):  
Ju-Sheng Zheng ◽  
Jian’an Luan ◽  
Eleni Sofianopoulou ◽  
Fumiaki Imamura ◽  
Isobel D. Stewart ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Vitamin C ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Genome Wide Association ◽  
Plasma Vitamin ◽  
Genome Wide ◽  
Randomization Analysis ◽  
European Populations

scholarly journals A Two-Sample Mendelian Randomization Analysis Investigates Associations between Gut Microbiota and Celiac Disease

2020 ◽  
Author(s):  
Iraia García-Santisteban ◽  
Ariadna Cilleros-Portet ◽  
Elisabet Moyua-Ormazabal ◽  
Alexander Kurilshikov ◽  
Alexandra Zhernakova ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Gut Microbiota ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Outcome Data ◽  
Mendelian Randomization Analysis ◽  
Genome Wide ◽  
Immune Mediated ◽  
And Function ◽  
Randomization Analysis

Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculate that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a Two-Sample Mendelian Randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous Genome Wide Association Study (GWAS) of gut microbiota, and outcome data from summary statistics of CeD GWAS and Immunochip studies. We have identified a number of putative associations between gut microbiota SNPs associated with CeD. Regarding bacterial composition, most of the associated SNPs are related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we have linked a number of SNPs to several bacterial metabolic pathways that seem to be related to CeD. Overall, this study represents the first 2SMR approach to elucidate the relationship between microbiome and CeD.

Von Willebrand disease and Weibel-Palade bodies

2010 ◽  
Vol 30 (03) ◽  
pp. 150-155 ◽  
Author(s):  
J. W. Wang ◽  
J. Eikenboom
Keyword(s):  
Platelet Adhesion ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Inflammatory Factors ◽  
Limited Data ◽  
Storage Organelle ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryVon Willebrand factor (VWF) is a pivotal haemostatic protein mediating platelet adhesion to injured endothelium and carrying coagulation factor VIII (FVIII) in the circulation to protect it from premature clearance. Apart from the roles in haemostasis, VWF drives the formation of the endothelial cell specific Weibel-Palade bodies (WPBs), which serve as a regulated storage of VWF and other thrombotic and inflammatory factors. Defects in VWF could lead to the bleeding disorder von Willebrand disease (VWD).Extensive studies have shown that several mutations identified in VWD patients cause an intracellular retention of VWF. However, the effects of such mutations on the formation and function of its storage organelle are largely unknown. This review gives an overview on the role of VWF in WPB biogenesis and summarizes the limited data on the WPBs formed by VWD-causing mutant VWF.

Baboon Fibrinogen Adsorption and Platelet Adhesion to Polymeric Materials

1991 ◽  
Vol 65 (05) ◽  
pp. 608-617 ◽  
Author(s):  
Joseph A Chinn ◽  
Thomas A Horbett ◽  
Buddy D Ratner
Keyword(s):  
Platelet Adhesion ◽  
Coagulation Factor ◽  
Polymeric Materials ◽  
Platelet Suspension ◽  
Perfusion Chamber ◽  
Static Conditions ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Fibrinogen Adsorption

SummaryThe role of fibrinogen in mediating platelet adhesion to polymers exposed to blood plasma was studied by comparison of the effect of plasma dilution on fibrinogen adsorption and platelet adhesion, and by the use of coagulation factor deficient plasmas. Polyetherurethane substrates were first preadsorbed with dilute plasma, then contacted with washed platelets suspended in a modified, apyrase containing Tyrode’s buffer. Platelet adhesion was studied under static conditions in Multiwell dishes, and also under shearing conditions using a parallel plate perfusion chamber. Fibrinogen adsorption and platelet adhesion were measured using 125I radiolabeled baboon fibrinogen and min radiolabeled baboon platelets, respectively. Surfaces were characterized by electron spectroscopy for chemical analysis (ESCA).When fibrinogen adsorption to Biomer was measured after 2 h contact with a series of dilute plasma solutions under static conditions, a peak in adsorption was observed from 0.26% plasma, i.e., adsorption was greater from 0.26% plasma than from either more or less dilute plasma. A peak in subsequent platelet adhesion to the plasma preadsorbed surfaces, measured after 2 h static incubation with washed platelets, was also observed but occurred on Biomer preadsorbed with 1.0% plasma.When fibrinogen adsorption was measured after 5 min contact under shearing conditions, the fibrinogen adsorption peak occurred on surfaces that had been exposed to 1.0% plasma. A peak in platelet adhesion to these preadsorbed surfaces, measured after 5 min contact with the platelet suspensions under shearing conditions, was observed on Biomer preadsorbed with 0.1% plasma. Shifts between the positions of the peaks in protein adsorption and platelet adhesion occurred on other polymers tested as well.Platelet adhesion was almost completely inhibited when baboon and human plasmas lacking fibrinogen (i. e., serum, heat defibrinogenated plasma, and congenitally afibrinogénémie plasma) were used. Platelet adhesion was restored to near normal when exogenous fibrinogen was added to fibrinogen deficient plasmas. Adhesion was also inhibited completely when a monoclonal antibody directed against the glycoprotein IIb/IIIa complex was added to the platelet suspension. Platelet adhesion to surfaces preadsorbed to von Willebrand factor deficient plasma was the same as to surfaces preadsorbed with normal plasma.While it appears that surface bound fibrinogen does mediate the initial attachment of platelets to Biomer, the observation that the fibrinogen adsorption and platelet adhesion maxima do not coincide exactly also suggests that the degree of subsequent platelet adhesion is dictated not only by the amount of surface bound fibrinogen but also by its conformation.

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